Textbook of Traumatic Brain Injury - part 10 pps

Alternative Treatments 691
B-vitamin supplement at double the usual adult dose, was
given to 75 patients age 55–85 years with mild dementia in
a 3-month DBRPC trial. The placebo group deteriorated.
In contrast, the Bio-Strath group showed improvement in
short-term memory with physical and emotional benefits
at 3 months (Pelka and Leuchtgens 1995). The relation-
ship between B vitamins and cognitive function persuades
us to treat brain-injured patients with B vitamins.
Homeopathy
A pilot study (at Spaulding Rehabilitation Hospital in
Boston) of 50 patients with mild TBI found that homeo-
pathic treatment significantly reduced the intensity of
patients’ symptoms (P=0.01) and reduced difficulty func-
tioning (P=0.0008) (Chapman et al. 1999). Limitations of
this study include the small number of patients, the vari-
ety of symptoms, duration of treatment, the use of differ-
ent combinations of multiple homeopathic preparations
in different patients, and questions about the validity and
reliability of the measures used (Chapman 2001). Never-
theless, the finding of statistically significant differences
in this PC study is intriguing. The investigators acknowl-
edged the need for a larger collaborative MC study to val-
idate these findings, but such a study has not been funded
as of this date. It is not possible to place this study within
TABLE 38–3. How to obtain quality alternative compounds
Compound Brand/company Source
Galantamine/Rhodiola A/P Formula/Ameriden 888-405-3336;
Huperzine-A GNC (General Nutrition Centers)
Centrophenoxine Lucidril/International Antiaging Systems (IAS) ; Fax: 011-44-
870-151-4145

Acetyl-
L-carnitine Life Extension Foundation (LEF) 800-544-4440;
Citicholine Smart Nutrition (SN); LEF
S-adenosylmethionine Donnamet/IAS See above
NatureMade (tosylate and butanedisulfonate) , pharmacies, chain
stores, buyer’s clubs, Costco, BJs
LEF See above
Pyritinol SN 800-479-2107;
Idebenone SN; Thorne Research 800-932-2953 (Thorne)
Vinpocetine LEF; SN; Intensive Nutrition See above
Rhodiola rosea Rosavin/Ameriden 888-405-3336;
Energy Kare/Kare-N-Herbs e=N-herbs.com
Rodax/Pinnacle GNC
Rhodiola Force/New Chapter Health food stores or online
Ginkgo Ginkgold/Nature’s Way Health food stores, pharmacies
Ginkoba/Pharmaton
Ginseng (Panax/
Korean)
Hsu’s Ginseng 800-388-3818;
Power Max 4x/Action Labs 800-932-2953
Piracetam (all
racetams)
IAS See above
L-Deprenyl Jumex tabs, Cyprenil (liquid)/IAS
Deprenyl, Selegiline, Eldepryl By prescription from U.S. pharmacies
B vitamins Bio-Strath/Nature’s Answer 800-681-7099 or health food stores
Note. This list of specific brands is not comprehensive. It simply represents easily available brands that we have used and found to be consistently of
good quality. Because brands and companies may change, the physician should reevaluate each product over time. See Table 38–4 for independent
evaluations of many brands and check www.consumerlab.com or www.supplementwatch.com.
692 TEXTBOOK OF TRAUMATIC BRAIN INJURY

the framework of the other treatments in this chapter
because the pathophysiological basis of homeopathy is
unproven. Biological effects are inferred from observa-
tions of change after treatment is administered. For a dis-
cussion of the state of homeopathic research, we refer the
reader to Alternative and Complementary Treatment in Neu-
rological Illness (Weintraub 2001).
Summary
Doctors and consumers are concerned about the quality
of herbs and nutrients. Advances in biochemistry have
improved the purity and stability of many products (Wag-
ner 1999). Although the publication of specific brands is
not the norm in a text of this kind, in the field of alterna-
tive medicine it is particularly important to choose prod-
ucts that have proven to be of good quality. To help clini-
cians find their way through the morass of unreliable,
ineffective lookalikes, Table 38–3 lists brands that we have
investigated. The following compounds in the brands we
have listed are pharmaceutical grade, regulated by Euro-
pean governmental agencies: centrophenoxine, acetyl-L-
carnitine, citicholine, S-adenosylmethionine (SAMe),
Picamilon, pyritinol, idebenone, vinpocetine, racetams,
and
L-deprenyl. The brands of the herbs, ginkgo, and
ginseng have been assessed by independent laboratories
as reported by ConsumerLab.com. The authors have per-
sonally contacted the manufacturers of Rhodiola rosea, gal-
antamine, and SAMe to obtain adequate information
regarding standardization, content, purity, and batch test-
ing procedures (including shelf life) to be reasonably

assured of the quality and reliability of these products.
Invariably, some products and companies will change
over time. Physicians should stay current by using unbi-
ased sources of product evaluation and rigorous studies.
Table 38–4 provides resources for those interested in reli-
able information on alternative compounds. Anyone
interested in an alternative product may contact the man-
ufacturer and request information about content, purity,
testing, and quality control, as well as consulting indepen-
dent sources of evaluation when available.
Alternative compounds can offer significant benefits
with few side effects in some patients with TBI. Certain
agents may help repair the nervous system and enhance
plasticity. In practice, it often requires several attempts to
design an effective combination of treatments. Many pa-
tients and families can participate in the development of
an alternative treatment regimen.
References
Ackerman PT, Dykman RA, Holloway C, et al: A trial of pirac-
etam in two subgroups of students with dyslexia enrolled in
summer tutoring. J Learn Disabil 24:542–549, 1991
al-Zuhair H, Abd el-Fattah A, el-Sayed MI: The effect of
meclofenoxate with ginkgo biloba extract or zinc on lipid
peroxide, some free radical scavengers and the cardiovascu-
lar system of aged rats. Pharmacol Res 38:65–72, 1998
Alvarez XA, Mouzo R, Pichel V, et al: Double-blind placebo-
controlled study with citicoline in APOE genotyped
Alzheimer’s disease patients: effects on cognitive perfor-
mance, brain bioelectrical activity and cerebral perfusion.
Methods Find Exp Clin Pharmacol 21:633–644, 1999

Amano T, Terao S, Imada I: Effects of 6-(10-hydroxydecyl)-2,3-
dimethoxy-5-methyl-1,4-benzoquinone (idebenone) and
related benzoquinones on porcine pancreas phospholipase
A
2
activity. Biol Pharm Bull 18:779–781, 1995
Anonymous: Acetyl-
L-carnitine. Altern Med Rev 4:438–441, 1999
Arciniegas DB: Traumatic brain injury and cognitive impair-
ment: the cholinergic hypothesis. Neuropsychiatry Re-
views 17–20, 2001
Arrigo A, Casale R, Buonocore M, et al: Effects of acetyl-
L-car-
nitine on reaction times in patients with cerebrovascular in-
sufficiency. Int J Clin Pharmacol Res 10:133–137, 1990
Bacci-Ballerini F, Lopez-Anguera A, Accarezy N, et al: Tra-
tiamiento del sindrome posconmocional con SAMe. Med
Clin (Barc) 80:161–164, 1983
TABLE 38–4. Resources for information on
alternative medicine
The Desktop Guide to Complementary and Alternative Medicine:
An Evidence Based Approach. Edited by Edzard Ernst. New
York, Mosby, 2001
Focus on Alternative and Complementary Therapies,
Pharmaceutical Press, P.O. Box 151, Wallingford, OX10
8QU, UK; Phone: +440 1491 829272; Fax: +440 1491 829292;

Martindale: The Complete Drug Reference. Pharmaceutical Press,
1 Lambeth High St., London SE17JN, UK
American Botanical Council, P.O. Box 144345, Austin, TX,

78714; Phone: 512-926-4900;
ConsumerLab,
FDA MedWatch, />Herb Research Foundation, 1007 Pearl St., Suite 200, Boulder,
CO 80302; Phone: 303-449-2265;
Natural Medicines Comprehensive Database, Therapeutic
Research Facility, 3120 W. March Lane, PO Box 8190,
Stockton, CA 95208; Phone: 209-472-2244; Fax: 209-472-
2249; ; http://
www.NaturalDatabase.com
Supplement Watch,
694 TEXTBOOK OF TRAUMATIC BRAIN INJURY
Fischhof PK, Saletu B, Ruther E, et al: Therapeutic efficacy of
pyritinol in patients with senile dementia of the Alzheimer
type (SDAT) and multi-infarct dementia (MID). Neuro-
psychobiology 26:65–70, 1992
Flicker L, Grimley-Evans G: Piracetam for dementia or cogni-
tive impairment (Cochrane Review). Cochrane Database
Syst Rev 2:CD0010112001
Furmanowa M, Oledzka H, Michalska M, et al: Rhodiola rosea L.
(Roseroot): in vitro regeneration and the biological activity
of roots, in Biotechnology in Agriculture and Forestry, Vol
33, in Medicinal and Aromatic Plants VIII. Edited by Bajaj
YPS. Berlin and Heidelberg, Germany, Springer-Verlag,
1995, pp 412–426
Furmanowa M, Skopinska-Rozewska E, Ragola E, et al: Rhodiola
rosea in vitro culture: phytochemical analysis and antioxi-
dant action. Acta Societatis Botanicorum Poloniae 67:69–
73, 1998
Galletti P, De Rosa M, Cotticelli MG, et al: Biochemical ratio-
nale for the use of CDPcholine in traumatic brain injury:

pharmacokinetics of the orally administered drug. J Neurol
Sci 103 (suppl):S19–25, 1991
Gillis JC, Benefield P, McTavish D: Idebenone: a review of its
pharmacodynamic and pharmacokinetic properties, and
therapeutic use in age-related cognitive disorders. Drugs
Aging 5:133–152, 1994
Gouliaev AH, Senning A: Piracetam and other structurally re-
lated nootropics. Brain Res Brain Res Rev 19:180–222,
1994
Gutzmann H, Hadler D: Sustained efficacy and safety of ide-
benone in the treatment of Alzheimer’s disease: update on
a 2-year double-blind multicentre study. J Neural Transm
Suppl 54:301–310, 1998
Hakkarainen H, Hakamies L: Piracetam in the treatment of
post-concussional syndrome: a double-blind study. Eur
Neurol 17:50–55, 1978
Hassing L, Wahlin A, Winblad B, et al: Further evidence of the
effects of vitamin B
12
and folate levels on episodic memory
functioning: a population-based study of healthy very old
adults. Biol Psychiatry 45:1472–1480, 1999
Hayes RL, Dixon CE: Neurochemical changes in mild head in-
jury. Semin Neurol 14:25–31, 1994
Herrmann WM, Kern U, Rohmel J: On the effects of pyritinol
on functional deficits of patients with organic mental disor-
ders. Pharmacopsychiatry 19:378–385, 1986
Hindmarch I, Fuchs HH, Erzigkeit H: Efficacy and tolerance of
vinpocetine in ambulant patients suffering from mild to
moderate organic psychosyndromes. Int Clin Psychophar-

macol 6:31–43, 1991
Huber W, Willmes K, Poeck K, et al: Piracetam as an adjuvant
to language therapy for aphasia: a randomized double-blind
placebo-controlled pilot study. Arch Phys Med Rehabil
78:245–250, 1997
Ishihara K, Katsuki H, Sugimura M, et al: Idebenone and vinpo-
cetine augment long-term potentiation in hippocampal
slices in the guinea pig. Neuropharmacology 28:569–573,
1989
Itil TM, Menon GN, Songar A, et al: CNS pharmacology and
clinical therapeutic effects of oxiracetam. Clin Neurophar-
macol 9 (suppl 3):S70–72, 1986
Itil TM, Eralp E, Ahmed I, et al: The pharmacological effects of
ginkgo biloba, a plant extract, on the brain of dementia pa-
tients in comparison with tacrine. Psychopharmacol Bull
34:391–397, 1998
Kang SY, Kim SH, Schini VB, et al: Dietary ginsenosides im-
prove endothelium-dependent relaxation in the thoracic
aorta of hypercholesterolemic rabbit. Gen Pharmacol
26:483–487, 1995
Kelly GS:
L-Carnitine: therapeutic applications of a condition-
ally essential amino acid. Altern Med Rev 3:345–360, 1998
Kessler J, Thiel A, Karbe H, et al: Piracetam improves activated
blood flow and facilitates rehabilitation of poststroke apha-
sic patients. Stroke 31:2112–2116, 2000
Kitamura K: Therapeutic effect of pyritinol on sequelae of head
injuries. J Int Med Res 9:215–221, 1981
Kitani K, Minami C, Maruyama W, et al: Common properties
for propargylamines of enhancing superoxide dismutase

and catalase activities in the dopaminergic system in the rat:
implications for the life prolonging effect of (-)deprenyl.
J Neural Transm Suppl (60):139–156, 2000
Knezevic S, Mubrin Z, Risberg J, et al: Pyritinol treatment of
SDAT patients: evaluation by psychiatric and neurological
examination, psychometric testing and rCBF measure-
ments. Int Clin Psychopharmacol 4:25–38, 1989
Knoll J: Outlines of a drug strategy to slow brain aging. Neuro-
psychopharmacologia Hungarica 11:151–170, 2000
Kurkin VA, Zapesochnaya GG: Khimicheskiy sostav i farmako-
logicheskiye svoystva rasteniy roda Rhodiola. Obzor.
[Chemical composition and pharmacological properties of
Rhodiola rosea] (Russian). Khim-Farm Zh [Chemical and
Pharmaceutical Journal Moscow] 20:1231–1244, 1986
Le Bars PL, Katz MM, Berman N, et al: A placebo-controlled,
double-blind, randomized trial of an extract of Ginkgo biloba
for dementia. North American EGb Study Group. JAMA
278:1327–1332, 1997
Leon-Carrion J, Dominguez-Roldan JM, Murillo-Cabezas F, et
al: The role of citicholine in neuropsychological training
after traumatic brain injury. NeuroRehabilitation 14:33–
40, 2000
Levin HS: Treatment of postconcussional symptoms with CDP-
choline. J Neurol Sci 103 (suppl):S39–42, 1991
Lolic MM, Fiskum G, Rosenthal RE: Neuroprotective effects of
acetyl-
L-carnitine after stroke in rats. Ann Emerg Med
29:758–765, 1997
Long DA, Ghosh K, Moore AN, et al: Deferoxamine improves
spatial memory performance following experimental brain

injury in rats. Brain Res 717:109–117, 1996
Lozano R: CDP-choline in the treatment of cranio-encephalic
traumata. J Neurol Sci 103 (suppl):S43–47, 1991
Lun A, Gruetzmann H, Wustmann C, et al: Effect of pyritinol
on the dopaminergic system and behavioural outcome in an
animal model of mild chronic postnatal hypoxia. Biomed
Biochim Acta 48:S237–242, 1989
PART VII
Prevention
This page intentionally left blank
699
39
Pharmacotherapy of
Prevention
Saori Shimizu, M.D., Ph.D.
Carl T. Fulp, M.S.
Nicolas C. Royo, Ph.D.
Tracy K. McIntosh, Ph.D.
NEUROPATHOLOGICAL INVESTIGATIONS
HAVE
classified traumatic brain injury (TBI) as either
focal or diffuse (Graham et al. 1995). Although focal in-
juries most often involve contusions and lacerations ac-
companied by hematoma (Gennarelli 1994), diffuse
brain swelling, ischemic brain damage, and diffuse ax-
onal injury are also considered to be major components
of the diffuse injury profile (Adams et al. 1989; Graham
et al. 1995; Maxwell et al. 1997). All TBIs can be further
stratified into primary injury (encompassing the imme-
diate, nonreversible mechanical damage to the brain),

and secondary or delayed injury, which represents a po-
tentially reversible process with a time of onset ranging
from hours to days after injury that progresses for weeks
or months (Graham et al. 1995). This secondary injury
process is a complex and poorly understood cascade of
interacting functional, structural, cellular, and molecu-
lar changes, including, but not limited to, impairment of
energy metabolism, ionic dysregulation, breakdown of
the blood–brain barrier (BBB), edema formation, activa-
tion and/or release of autodestructive neurochemicals
and enzymes, changes in cerebral perfusion and intra-
cranial pressure (ICP), inflammation, and pathologic/
protective changes in intracellular genes and proteins
(Figure 39–1). Although these events may lead to de-
layed cell death and/or neurological dysfunction, the de-
layed onset and reversibility of secondary damage offer
a unique opportunity for targeted therapeutic pharma-
cological intervention to attenuate cellular damage and
functional recovery during the chronic phase of the in-
jury (McIntosh et al. 1998).
It is now well established that several clinically relevant
experimental TBI models mimic many aspects of behav-
ioral impairment and histopathological damage reported
after human brain injury (for review see Laurer et al. 2000).
Moreover, these experimental models provide us with the
unique opportunity to both identify and investigate the
pathophysiological changes triggered by TBI and target
these pathways using new pharmacological strategies. As
the pathophysiological sequelae of TBI are multifactorial,
the development and characterization of new compounds

remains extremely challenging. This chapter reviews some
of the more promising neuroprotective strategies studied
to date in clinical and preclinical settings.
Excitatory Amino Acid Antagonists
Pathologic release of the excitatory amino acid (EAA)
neurotransmitters glutamate and aspartate and subse-
quent activation of specific glutamate receptors result in
increased neuronal influx of cations (sodium and calcium)
into the cell (Figure 39–2). This ionic influx may damage
or destroy cells (i.e., excitotoxicity) through direct or
indirect pathways (Olney et al. 1971). Both experimental
and clinical brain injury induce an acute and potentially
neurotoxic increase in extracellular glutamate concentra-
tions (Faden et al. 1989; Globus et al. 1995; Katayama et
700 TEXTBOOK OF TRAUMATIC BRAIN INJURY
al. 1989, 1990; Nilsson et al. 1990; Palmer et al. 1993;
Panter et al. 1992). Although most experimental studies
have suggested that the posttraumatic rise in extracellular
glutamate is of short duration, clinical studies have
reported that glutamate concentrations are significantly
elevated in the cerebrospinal fluid (CSF) of brain-injured
patients for several days or perhaps weeks (Baker et al.
1993; Palmer et al. 1994).
Regional distribution of both N-methyl-D-aspartate
(NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-
propionate/kainic acid (AMPA/KA) receptors has been di-
rectly related to the selective vulnerability of specific brain
regions caused by CNS injury (for review see Choi 1990).
Miller et al. (1990) reported an acute decrease in NMDA but
not AMPA/KA receptor binding in the hippocampal CA1

stratum radiatum, the molecular layer of the dentate gyrus,
and the outer (1–3) and inner (5–6) layers of the neocortex
within 3 hours after TBI in the rat. The hippocampus, which
plays a prominent role in learning and memory, possesses a
high density of glutamate receptors (Monaghan and Cot-
man 1986). Cognitive dysfunction, including a suppression
of long-term potentiation and deficits in learning and mem-
ory, has been reported after TBI (for review see Albensi
2001). Sun and Faden (1995b) demonstrated that pretreat-
ment with antisense oligodeoxynucleotides directed against
the NMDA-R1 receptor subunit enhances survival and neu-
rological motor recovery after TBI in rats. These studies un-
FIGURE 39–1. Cascade of secondary damaging
events in experimental traumatic brain injury.
FIGURE 39–2. Glutamate receptor subtypes: N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionate (AMPA)/kainate.
APV=2-amino-5-phosphovaleric acid; CPP=3-(2-carboxypiperizin-4yl)-propyl-1-phosphonic acid; I2CA=indole-2-carboxylic acid.
Pharmacotherapy of Prevention 701
derscore the potentially important role of the NMDA re-
ceptor in mediating part of the pathological response to
brain trauma (Table 39–1).
Although competitive NMDA receptor antagonists
are logical candidates for the treatment of traumatic CNS
injury, most of the early-generation compounds such as
2-amino-5-phosphovaleric acid (APV) and 3-(2-carbox-
ypiperizin-4yl)-propyl-1-phosphonic acid (CPP) were
strongly lipophobic and possessed poor BBB permeabil-
ity, resulting in the necessity for direct CNS administra-
tion. Intracerebral administration of CPP was shown to
improve neurological outcome (Faden et al. 1989), and

intracerebroventricular APV administration was reported
to reverse hypermetabolism after TBI in rats (Kawamata
et al. 1992). In addition, CPP has recently been shown to
increase apoptotic damage despite its ability to decrease
excitotoxic cell damage in a model of TBI in the develop-
ing rat (Pohl et al. 1999).
More recently developed competitive NMDA antag-
onists such as Selfotel (CGS-19755 or cis-4-[phospho-
methyl]-2-piperidine carboxylic acid), LY233053 ([1]-
[2SR,4RS]-4-[1H-tetrazol-5-ylmethyl] piperidine-2-car-
boxylic acid), and CP101,606 ([1S, 29]-1-[4-hydroxyphe-
nyl]-2-[hydroxy-4-phenylpiperidino]-1-propanol), an
NR2B-selective NMDA receptor antagonist, have been
shown to have greater BBB permeability than earlier gen-
erations of similar compounds (Menniti et al. 1995).
Although Selfotel has shown no beneficial effects on
behavioral outcome, administration of this antagonist has
been reported to reduce trauma-induced extracellular
glutamate release in rats (Panter and Faden 1992). On the
basis of this and other published data from experimental
models of ischemia, a multicenter trial of Selfotel was ini-
tiated in the United States and Europe but was prema-
turely terminated because of side effects associated with
competitive NMDA antagonism (Bullock 1995). Admin-
istration of CP101,606 and its stereoisomers has been
shown to attenuate both cognitive dysfunction and re-
gional cerebral edema in TBI in the rat (Okiyama et al.
1997, 1998). The CP101,606 compound is currently in
Phase II trials in the United States and in Phase I trials in
Japan for the potential treatment of brain injury and has

been shown to be well tolerated and able to penetrate
CSF and brain (Bullock et al. 1999; Merchant et al. 1999).
In the initial pilot studies, mild to moderately head-in-
jured patients did not exhibit differences in performance
on the Neurobehavioral Rating Scale or Kurtzke Scoring
(Merchant et al. 1999), whereas severely head-injured pa-
tients who were treated with the CP101,606 compound
presented with, on average, better Glasgow Outcome
Scores (Bullock et al. 1999).
Noncompetitive NMDA receptor antagonists also ap-
pear to have efficacy in the treatment of TBI. Hayes et al.
(1988) first reported that pretreatment with the dissocia-
tive anesthetic and noncompetitive NMDA antagonist
phencyclidine (PCP) attenuated neurological motor defi-
cits after TBI in rats. Similar results were obtained with
prophylactic treatment using dizocilpine (MK-801)
(McIntosh et al. 1990). Treatment with MK-801 after
TBI in rats also improved brain metabolic function and
restored magnesium homeostasis (McIntosh et al. 1990),
and administration of higher doses improved neurological
motor deficits and reduced regional cerebral edema (Sha-
pira et al. 1990). Pretreatment with MK-801 was found to
attenuate the extracellular rise in glutamate associated
with closed head injury followed by hypoxia in rats (Katoh
et al. 1997) and enhance the recovery of spatial memory
performance in animals subjected to combined TBI and
entorhinal cortical lesions (Phillips et al. 1997). Adminis-
tration of the noncompetitive NMDA antagonists dextro-
phan and dextromethorphan improved brain metabolic
state, attenuated neurological motor deficits, and reduced

the postinjury decline in brain magnesium concentrations
observed after TBI in rats (Faden et al. 1989). Golding
and Vink (1995) reported that dextromethorphan im-
proved brain bioenergetic state and restored brain magne-
sium homeostasis after TBI in rats. Dextrophan also im-
proved neurologic motor function and reduced edema after
TBI in rats (Shohami et al. 1993). The NMDA-associated
channel blocker ketamine has also been shown to improve
posttraumatic cognitive outcome (Smith et al. 1993a),
maintain both calcium and magnesium homeostasis (Sha-
pira et al. 1993), and reduce expression of several immedi-
ate early genes (IEGs) induced in cerebral cortex and hip-
pocampal dentate gyrus after TBI in rats (Belluardo et al.
1995). Gacyclidine, a more recently discovered phencyc-
lidine derivative that acts as a noncompetitive NMDA an-
tagonist (Hirbec et al. 2000), reduced lesion volume and
improved neuronal survival and motor function when ad-
ministered intraparenchymally after TBI (Smith et al.
2000). Although administration of the high-affinity,
noncompetitive NMDA receptor antagonist CNS1102
(Aptiganel or Cerestat) was shown to attenuate contu-
sion volume and hemispheric swelling after TBI in rats
(Kroppenstedt et al. 1998), a clinical trial of this drug was
prematurely terminated because of high mortality rates in
an associated stroke trial. Although few studies have eval-
uated the potential neuroprotective effects of noncompet-
itive NMDA antagonists in models of brain trauma, Smith
et al. (1997) reported that the NMDA receptor-associated
ionophore blocker remacemide (2-amino-N-[1-methyl-
1,2-diphenylethyl] acetamide hydrochloride) also signifi-

702 TEXTBOOK OF TRAUMATIC BRAIN INJURY
TABLE 39–1. Excitatory amino acid antagonists and agonists classified according to binding site
Compound
Type of
research Outcome References
NMDA antagonist
Competitive APV e ↓ glucose utilization Kawamata et al. 1992
CPP e ↑ motor function, apoptotic
damage; ↓ necrosis
Faden et al. 1989; Pohl et al. 1999
Selfotel e,c ↑ bioenergetic state, Mg
2+

homeostasis
Bullock 1995; Juul et al. 2000;
Morris et al. 1998; Panter et al.
1992
CP101,606 e,c ↑ cognitive function; ↓ cell
death, edema
Bullock et al. 1999; Merchant et al.
1999; Okiyama et al. 1997, 1998
Noncompetitive Phencyclidine e ↑ motor function Hayes et al. 1988
MK-801 e ↑ bioenergetic state, Mg
2+

homeostasis, motor/
cognitive function; ↓edema,
glutamate release
Katoh et al. 1997; McIntosh et al.
1990; Phillips et al. 1997; Shapira

et al. 1990
Dextrophan e ↑ bioenergetic state, motor
function, Mg
2+
homeostasis;
↓ edema
Faden et al. 1989
Dextromethorphan e ↑ bioenergetic state, motor
function, Mg
2+
homeostasis
Faden et al. 1989; Golding et al.
1995
Ketamine e ↑ cognitive function,
Mg
2+
,Ca
2+
homeostasis;
↓ immediate early genes
Belluardo et al. 1995; Shapira et al.
1993; Smith et al. 1993a
Gancyclidine e ↑ motor function; ↓ cell death,
lesion volume
Hirbec et al. 2001; Smith et al.
2000
Cerestat e,c ↓ edema, lesion volume;
↑ psychomotor side effect
Kroppenstedt et al. 1998; Muir et
al. 1995

Remacemide
hydrochloride
e ↓ lesion volume Smith et al. 1997
NMDA glycine site I2CA e ↑ motor/cognitive function;
↓ edema
Smith et al. 1993b
NMDA Mg
2+
site MgCl
2
e ↑ motor/cognitive function;
↓edema
Bareyre et al. 2000; Heath and
Vink 1998; McIntosh et al. 1989;
Okiyama et al. 1995; Saatman et
al. 2001; Smith et al. 1993a
MgSO
4
e ↑ motor/cognitive function;
↓ edema
Heath and Vink 1998; McIntosh
et al. 1988
NMDA polyamine site Ifenprodil e ↓ edema, BBB breakdown Okiyama et al. 1998
Eliprodil e ↑ cognitive function; ↓ lesion
volume
Hogg et al. 1998
ODC inhibitor DFMO e ↑ cognitive function; ↓ edema,
ODC
Baskaya et al. 1996
mGluR1 antagonist AIDA e ↑ motor/cognitive function;

↓ cell death, lesion volume
Faden et al. 2001; Lyeth et al. 2001
Pharmacotherapy of Prevention 703
cantly reduced posttraumatic cortical lesion volume after
TBI in rats.
The magnesium ion functions as a key endogenous
modulator of the NMDA receptor, and its essential roles
in many bioenergetic and cellular metabolic and genomic
processes makes it an attractive candidate for use in the
treatment of TBI. The loss of intracellular magnesium
concentrations after experimental TBI (Shohami et al.
1993; Vink et al. 1996) suggests that replacement therapy
using this ionic salt may have therapeutic value. Both pre-
and postinjury treatment with magnesium salts (MgCl
2
or
MgSO
4
) has been demonstrated to improve neurological
motor and cognitive deficits and decrease regional cere-
bral edema formation (Bareyre et al. 2000; McIntosh et al.
1988, 1989; Okiyama et al. 1995; Saatman et al. 2001;
Shapira et al. 1993; Smith et al. 1993a). Because of this
documented efficacy in experimental trauma models, a
single-center National Institutes of Health–sponsored
clinical trial in severely injured TBI patients has been ini-
tiated in the United States.
Other strategies to block NMDA-receptor associated
neurotoxicity involve blockade or modulation of the
NMDA receptor–associated glycine sites and/or

polyamine binding sites. One selective glycine site antago-
nist, indole-2-carboxylic acid (I2CA), has been shown to
improve behavioral outcome and reduce edema after TBI
in rats (Smith et al. 1993b). Two broad-spectrum glutamate
antagonists, kynurenate (KYNA) and 6-cyano-7-nitroqui-
noxaline-2,3-dione (CNQX), which antagonize both the
glycine site and AMPA/KA receptors with varying affinity,
have also been shown to be efficacious in reducing post-
traumatic metabolic and neurobehavioral dysfunction in
experimental TBI (Kawamata et al. 1992; Smith et al.
1993b). Postinjury administration of KYNA reduced the
posttraumatic loss of hippocampal neurons after TBI in the
rat (Hicks et al. 1994). Inhibition of the ornithine decar-
mGluR1/2 antagonist MCPG e ↓ cell death Gong et al. 1995; Mukhin et al.
1996
mGluR2 agonist LY354740 e ↑ motor function Allen et al. 1999
DCG-IV e ↓ cell death Zwienenberg et al. 2001
mGluR3 agonist CPPG e No effect Zwienenberg et al. 2001
mGluR5 antagonist MPEP e ↑ motor/cognitive function;
↓ lesion volume
Movsesyan et al. 2001
Inhibition of Glu
release
Lamotrigine e,c ↓ glutamate release Miller et al. 1986; Showalter and
Kimmel 2000
BW1003C87 e ↓ edema Okiyama et al. 1995
619C89 e,c ↑ motor/cognitive function;
↓ cell death, gliosis
Sun et al. 1995; Voddi et al. 1995
Riluzole e ↑ motor/cognitive function;

↓ edema, lesion volume,
glutamate release
Bareyre et al. 1997; McIntosh et al.
1996; Stover et al. 2000; Wahl et
al. 1997; Zhang et al. 1998
AMPA/KA antagonist KYNA e ↑ cognitive function; ↓ cell
death, edema
Hicks et al. 1994; Smith et al.
1993b
Competitive CNQX e ↓ glucose utilization Kawamata et al. 1990, 1992
NBQX e ↓ cell death Bernert and Turski 1996;
Ikonomidou and Turski 1996;
Ikonomodou et al. 1996, 2000
Noncompetitive GYKI-52466 e ↑ cognitive function; ↓ cell
death
Hylton et al. 1995
Talampanel e ↓ cell death Belayev et al. 2001
Note. BBB=blood–brain barrier; c=clinical trial; e=experimental study; NMDA = N-methyl-D-aspartate.
TABLE 39–1. Excitatory amino acid antagonists and agonists classified according to binding site (continued)
Compound
Type of
research Outcome References
704 TEXTBOOK OF TRAUMATIC BRAIN INJURY
boxylase (ODC) enzyme using difluoromethylornithine
(DFMO) has been shown to reduce regional cerebral
edema after TBI in rats (Baskaya et al. 1996), and compet-
itive antagonism of the NMDA-associated polyamine
binding site by ifenprodil and its derivative eliprodil (SL
82.0715) has also been reported to exert beneficial effects
after experimental TBI (Toulmond et al. 1993).

Although the NMDA receptor is implicated as play-
ing an important role in mediating part of the pathologi-
cal response to brain trauma, AMPA antagonists have also
been used therapeutically with some success. Administra-
tion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)qui-
noxaline (NBQX) has been shown to prevent hippocam-
pal cell loss after brain trauma in adult but not immature
rats (Bernert and Turski 1996; Ikonomidou and Turski
1996; Ikonomidou et al. 1996). The compound GYKI-
52466 (1-[4-aminophenyl]-4-methyl-7,8-methylenedio-
ixy-5H-2,3-benzodiazepine), a noncompetitive AMPA/
KA antagonist, markedly improved cognitive function af-
ter TBI in the rat (Hylton et al. 1995). More recently, an
orally active, noncompetitive AMPA antagonist, (R)-7-
acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-
1,3-dioxolo(4,5-h)(2,3) benzodiazepine (Talampanel) has
also been shown to significantly attenuate neuronal CA1
cell loss when administered after TBI (Belayev et al.
2001).
Elevated concentrations of extracellular glutamate af-
ter TBI activate metabotropic receptors (mGluRs), in ad-
dition to ionotropic receptors, and a number of recent
studies implicate activation of mGluRs in acute TBI path-
ology (Faden et al. 1997; Gong et al. 1995, 1999; Mukhin
et al. 1996, 1997). Eight mGluR subtypes have been clas-
sified, and these have been divided into three major
classes on the basis of sequence homology, signal trans-
duction pathways, and pharmacological sensitivity (Pin
and Duvoisin 1995; Schoepp et al. 1999). A differential
role for the different subgroups of mGluRs in posttrau-

matic cell death and survival has been proposed, and the
blockade of group I or the activation of group II or group
III receptors seems to be a beneficial strategy after TBI.
On the basis of the use of antisense oligonucleotides and
less selective group I antagonists such as (S)-α-methyl-4-
carboxyphenylglycine (MCPG), a drug that acts as both a
group I and group II antagonist, it has been suggested
that mGluR1 activation contributes to traumatic cell
death (Gong et al. 1995; Mukhin et al. 1996). Administra-
tion of (R,S)-1-aminoindan-1,5-dicarboxylic acid
(AIDA), a selective mGluR1 antagonist, resulted in sig-
nificant improvement in motor and cognitive function
and reduction in the numbers of degenerating neurons
and in lesion volume when administered after TBI (Faden
et al. 2001; Lyeth et al. 2001). Although comparable re-
sults were obtained with administration of 2-methyl-6-
(2-phenylethenyl)-pyridine (MPEP), a specific mGluR5
antagonist, it was suggested that the therapeutic utility of
this drug may reflect its ability to modulate NMDA re-
ceptor activity rather than its ability to act as an mGluR5
agonist (Movsesyan et al. 2001). A number of laboratories
have recently produced evidence that activation of group
I mGluRs may reduce apoptotic cell death in models ex-
hibiting neuronal apoptosis but increase necrotic cell
death in vitro (Allen et al. 2000). The mechanism under-
lying the apparent dual neurotoxic/neuroprotective ef-
fects of group I mGluR activation remains unidentified.
With respect to group II and III mGluRs, postinjury
administration of LY354740, a specific group II mGluR
agonist, significantly improved neurological outcome af-

ter TBI in experimental animals with apparently fewer
side effects and better tolerance than those associated
with NMDA receptor antagonists (Allen et al. 1999). Ad-
ministration of the group II mGluR2 agonist 2-(2',3')-
dicarboxycyclopropylglycine (DCG-IV) directly into the
hippocampus after TBI in rats resulted in a decrease in
the number of degenerating neurons in the CA2 and CA3
regions (Zwienenberg et al. 2001), although hippocampal
administration of (R,S)-alpha-cyclopropyl-4-phospho-
nophenylglycine (CPPG), a group III agonist, failed to
protect CA2 or CA3 hippocampal neurons (Zwienenberg
et al. 2001). A combination of MK-801 and the group III
agonist L-(+)2 amino-4-phosphobutyric acid (L-AP4)
provided enhanced neuroprotection compared with
NMDA blockade alone after experimental TBI
(Zwienenberg et al. 2001). Taken together, these data
suggest that treatment with agents influencing the differ-
ent subclasses of mGluRs may be beneficial after brain
trauma.
Given the apparent failure of postsynaptic glutamate
antagonist clinical trials, one novel strategy to attenuate
glutamatergic neurotoxicity after brain trauma may be to
use pharmacological agents that function presynaptically
to inhibit glutamate release. The compound lamotrigine
(3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) and
its derivatives BW 1003C87 (5-[2,3,5-trichlorophenyl]
pyrimidine-2,4-diamine ethane sulphonate), 619C89 (4-
amino-2-[4-methyl-1-piperazinyl]-5-[2,3,5-trichlo-
rophenyl] pyrimidine mesylate monohydrate), and rilu-
zole all inhibit veratrine- but not potassium-stimulated

glutamate release, presumably by reducing ion flux
through voltage-gated sodium channels with subsequent
attenuation of glutamate release (Miller et al. 1986). Pre-
injury treatment with 619C89 has been shown to reduce
neuronal loss in CA1 and CA3 hippocampal pyramidal
cells after TBI in rats (Sun and Faden 1995a), whereas
postinjury treatment with BW1003C87 can attenuate re-
Pharmacotherapy of Prevention 705
gional cerebral edema and improve neurobehavioral
function (Okiyama et al. 1995; Voddi et al. 1995). Treat-
ment with riluzole after TBI significantly attenuated both
cognitive and motor deficits (McIntosh et al. 1996), re-
duced cerebral edema (Bareyre et al. 1997; Stover et al.
2000a), and reduced posttraumatic lesion volume (Wahl
et al. 1997; C. Zhang et al. 1998). The use of presynaptic
inhibitors of glutamate release, such as riluzole, in clinical
brain injury may present a possible alternative to the use
of postsynaptic glutamate antagonists, which are known
to be associated with neurotoxicity and psychomimetic
side effects.
Inhibition of Lipid Peroxidation
Oxidative damage has been implicated in many of the
pathological changes that occur after TBI (Ercan et al.
2001; Hsiang et al. 1997). Oxidative damage in the CNS
manifests itself primarily as lipid peroxidation because the
brain is rich in peroxidizable fatty acids and possesses rel-
atively few antioxidant defense systems (for review see
Floyd 1999). After TBI, alterations in regional cerebral
blood flow (CBF) and reductions in substrate delivery
likely combine to produce intracellular arachidonic acid

cascade metabolites and reactive oxygen species (ROS)
(Ikeda and Long 1990; Kontos and Povlishock 1986).
The genesis of ROS after TBI has also been related to
nonischemic events, including the increase in intracellu-
lar calcium concentrations that induces ROS release from
mitochondria (Tymianski and Tator 1996). Other endog-
enous ROS also occur from enzymatic processes, mono-
amine oxidase, cyclooxygenase (COX), nitric oxide syn-
thase (NOS), and nicotine adenine dinucleotide
phosphate oxidase, as well as macrophages and neutro-
phils. Excessive glutamate release can also generate high
levels of ROS (Dugan and Choi 1994). These ROS cause
peroxidative destruction of the lipid bilayer cell mem-
brane, oxidize cellular proteins and nucleic acids, and
attack the cerebrovasculature, thereby affecting the BBB
integrity and/or vascular reactivity. Several regulatory
mechanisms can be affected by ROS, including activation
of cytokine or growth factor–mediated signal transduc-
tion pathways, induction of IEGs, and disruption of cal-
modulin-regulated gene transcription (Yao et al. 1996).
Free reactive iron, a catalyst for the formation of ROS,
may also be involved in trauma-induced peroxidative tis-
sue damage.
Several studies have indirectly demonstrated the early
generation of superoxide radicals in injured brains, which
subsequently resulted in secondary damage to the brain
microvasculature (Povlishock and Kontos 1992). Some
investigators have used spin trap probes of salicylate trap-
ping methods to demonstrate an early posttraumatic for-
mation of hydroxyl radicals in injured brains (Hall et al.

1993) that also correlated with the development of BBB
disruption (Smith et al. 1994). Still others have used cy-
clic-voltammetry techniques to measure the production
of low-molecular-weight antioxidants (LMWAs) by the
injured brain as another indirect indication of ROS pro-
duction after brain trauma (Beit-Yannai et al. 1997; Sho-
hami et al. 1997b). These studies suggest that LMWAs
are mobilized from brain cells to the extracellular space
(Moor et al. 2001). More stable molecules such as 3,4-
dihydroxybenzoic acid (3,4-DHBA) have been used to de-
tect an increase in ROS with microdialysis after TBI
(Marklund et al. 2001a). Recently, isoprostanes have been
used as specific markers to detect lipid peroxidation after
TBI (Tyurin et al. 2000); in one study, 8,12-iso-IPF
2α
-VI
levels increased in brain and blood between 1 and 24
hours after TBI (Pratico et al. 2002).
Posttraumatic alterations in intracellular calcium pre-
cipitate an attack on the cellular cytoarchitecture via acti-
vation of calpains and lipases and also induce the formation
of ROS that attack the cell membrane. Trauma-induced
activation of phospholipases A
2
(PLA2) and C (PLC) re-
sults in the release of free fatty acids, diacylglycerol
(DAG), thromboxane B
2
, and leukotrienes, whereas accu-
mulation of free arachidonic acid itself may affect mem-

brane permeability (for a review see Bazan et al. 1995).
TBI-induced DAG formation is associated with posttrau-
matic cerebral edema (Dhillon et al. 1994, 1995), and
DAG activates protein kinase C, which may modulate
other signal transduction pathways. Protein kinase C in-
creases over time in the cortex and hippocampus after
TBI in the rat (Sun and Faden 1994). Homayoun et al.
(1997) reported that TBI in rats induces a delayed and
sustained activation of phospholipase-mediated signaling
pathways, leading to membrane phospholipid degrada-
tion that targets docosahexaenoyl phospholipid-enriched
membranes.
Compounds that block various steps in the arachido-
nate cascade have been shown to be somewhat effective in
experimental models of TBI (Table 39–2). The nonselec-
tive COX inhibitors ibuprofen and indomethacin have
been shown to improve neurologic function and to de-
crease mortality after TBI (Hall 1985; Kim et al. 1989).
Head-injured patients who have received intravenous in-
domethacin present with reduced ICP and CBF and in-
creased cerebral perfusion pressure (Slavik and Rhoney
1999). COX-2 levels have been shown to be elevated in
injured cortex and in the ipsilateral hippocampus after
experimental TBI in rats (Dash et al. 2000). Although
administration of selective COX-2 inhibitors 4-(5-[4-
706 TEXTBOOK OF TRAUMATIC BRAIN INJURY
TABLE 39–2. Antioxidant, antiinflammatory, and neurotrophic factors
Type of agent Compound
Type of
research Outcome References

COX inhibitor Indomethacin e,c ↓ ICP Slavik et al. 1999
COX-2 inhibitor Celecoxib e ↑ cognitive function; ↓ motor
function
Dash et al. 2001
Nimesulide e ↑ motor/cognitive function Cernak et al. 2001
SC 58125 e ↓ antioxidants Tyurin et al. 2000
Iron chelator Deferoxamine e ↑ motor function; ↓ tissue SOD Panter et al. 1992
Desferal e ↑ motor/cognitive function;
↓ edema
Ikeda et al. 1989; Zhang et al.
1998
Antioxidant U-101033E e ↓ mitochondria dysfunction Xiong et al. 1997
SOD e ↓ edema Shohami et al. 1997
PEG-SOD e,c ↑ motor function, BBB
penetration; ↓ ARDS
Hamm et al. 1996; Muizelaar
et al. 1993; Young et al.
1996
PC-SOD e ↓ edema Yunoki et al. 1997
PBN e ↑ cognitive function; ↓ lesion
volume, tissue loss
Marklund et al. 2001
S-PBN e ↓ tissue loss Marklund et al. 2001
LY341122 e ↓ cell death, lesion volume Wada et al. 1999
21-aminosteroid Freedox e ↑ motor function, metabolism;
↓ edema, mortality
Hall et al. 1988, 1994;
McIntosh et al. 1992;
Sanada et al. 1993
U-743896 e ↓ axonal injury Marion and White 1996

NOS inhibitor BN 80933 e ↑ sensory/motor function Chabrier et al. 1999
ICAM-1 inhibitor 1A29 e No change Isaksson et al. 2001
Leukocyte adherence inhibition Prostacyclin e ↓ cell death Allan et al. 2001
IL-1ra IL-1ra e ↑ cognitive function; ↓ cell
death
Knoblach et al. 2000;
Sanderson et al. 1999;
Toulmond et al. 1995
Tetracycline Minocycline e ↑ motor function; ↓ lesion
volume
Fink et al. 1999; Sanchez
Mejia et al. 2001
IL-10 IL-10 e ↑ motor function; ↓ TNF
expression
Knoblach et al. 1998
Immunosuppressant
Pentoxifylline e ↑ motor function; ↓ edema Shohami et al. 1996
Kallikrein-kinin CP-0127 e,c ↑ GCS; ↓ edema, mortality Marmarou et al. 1999;
Narotam et al. 1998;
B
2
receptor antagonist Lf-16-068Ms e ↓ edema Stover et al. 2000a, 2000b
Endocannabinoid 2-AG e ↓ edema Panikashvili et al. 2001
Dexabinol c ↓ ICP/CPP Pop 2000
Neutrophic factors NGF e ↑ cognitive function,
cholinergic reinnervation;
↓ cell death
Philips et al. 2001
Pharmacotherapy of Prevention 707
methylphenyl]-3-[trifluoromethyl]-1H-pyrazol-1-yl)

benzenesulfonamide (celecoxib) and nimesulide was
shown to improve cognitive function after TBI, its effect
on motor function remains controversial (Hurley et al.
2002). The COX-2 inhibitor SC 58125 prevented deple-
tion of antioxidants after TBI in rats (Tyurin et al. 2000).
Although COX-2 induction after TBI may result in selec-
tive beneficial responses, chronic COX-2 production may
actually potentiate free radical–mediated cellular damage,
vascular dysfunction, and alterations in cellular metabo-
lism (Strauss et al. 2000).
Experimental work suggests that ROS scavengers may
confer some neuroprotection in experimental models of
TBI (Hensley et al. 1997; Shohami et al. 1997a). Antiox-
idants such as α-tocopherol (vitamin E) have been shown
to be beneficial in TBI (Clifton et al. 1989; Stein et al.
1991; Conte et al. 2004). Conversely, Stoffel and col-
leagues (1997) have reported that increasing plasma vita-
min E levels had no effect on posttraumatic vasogenic
brain edema. It has been reported that systemic levels of
two major antioxidants, vitamin E and ascorbic acid (vita-
min C), were significantly reduced in injured rats after
TBI and that these reductions inversely correlated with
isoprostane levels (Pratico et al. 2002).
Panter et al. (1992) reported that administration of
the iron chelator dextran-deferoxamine, which protects
brain tissue by terminating radical-chain reactions and re-
moving intracellular superoxide, improved neurological
impairment after TBI in mice, suggesting that brain in-
jury is associated with significant iron-dependent ROS-
induced lipid peroxidation. Desferal, another potent che-

lator of redox-active metals, has been shown to attenuate
brain edema and improve neurological recovery after TBI
in rats (Ikeda et al. 1989; R. Zhang et al. 1998). Adminis-
tration of the novel antioxidant pyrolopyrimidine (U-
101033E) after TBI in the rat was also shown to reduce
mitochondrial dysfunction.
The use of stable nitroxide radicals as antioxidant
therapy in CNS injury has also been attempted. Nitrox-
ides, which are cell-permeable, nontoxic, stable radicals,
have been shown to prevent ROS-induced lipid peroxida-
tion (Krishna et al. 1996; Pogrebniak et al. 1991). Admin-
istration of these compounds markedly improved neuro-
logical recovery, reduced edema, and protected the
impaired BBB after TBI in rats (Beit-Yannai et al. 1996).
Administration of nitrone radical scavengers, another
class of potent ROS, has been evaluated for neuroprotec-
tive efficacy after TBI. Administration of α-phenyl-tert-
N-butyl nitrone (PBN) or 2-sulfo-phenyl-N-tert-butyl
nitrone (S-PBN) in rats significantly reduced ROS for-
mation, cognitive impairment, and lesion volume after
TBI (Marklund et al. 2001b, 2001c, 2001d). Other ROS
scavengers that recently have been demonstrated to exert
neuroprotective effects in experimental TBI include the
second-generation azulenyl nitrone stilbazulenyl nitrone
(STAZN) (Belayev et al. 2002), melatonin (Sarrafzadeh et
al. 2000), a superoxide radical scavenger (OPC-14117)
(Aoyama et al. 2002; Mori et al. 1998) 2-(3,5-di-t-butyl-
4-hydroxyphenyl)-4-(2-[4-methylethylaminomethyl-
phenyloxy]ethyl)oxazole LY341122 (Wada et al. 1999),
and citicoline, an endogenous intermediate of phosphati-

dylcholine synthesis reported to stabilize the cell mem-
brane integrity and free fatty acid formation (Baskaya et
al. 2000).
BDNF e No change Blaha et al. 2000
GDNF e ↓ cell death, lesion volume Hermann et al. 2001; Kim et
al. 2001
bFGF e ↑ cognitive function; ↓ cell
death
Dietrich et al. 1996;
McDermott et al. 1997;
Yang et al. 2000
IGF-1 e,c ↑ motor/cognitive function Hatton et al. 1997; Saatman
et al. 1997
Note. ARDS=adult respiratory distress syndrome; BBB=blood–brain barrier; BDNF=brain-derived neurotrophic factor; bFGF=basic fibroblast
growth factor; c=clinical trial; COX=cyclooxygenase; CPP=cerebral perfusion pressure; e=experimental study; FGF= fibroblast growth factor;
GDNF=glial cell-line–derived neurotrophic factor; ICAM-1=intercellular adhesion molecule-1; ICP=intracranial pressure; IGF=insulin-like growth
factor; IL=interleukin; NGF=nerve growth factor; NOS=nitric oxide synthase; PC-SOD=lecithinized superoxide dismutase; PEG-
SOD=polyethylene glycol superoxide dismutase; SOD = superoxide dismutase; TNF = tumor necrosis factor.
TABLE 39–2. Antioxidant, antiinflammatory, and neurotrophic factors (continued)
Type of agent Compound
Type of
research Outcome References
708 TEXTBOOK OF TRAUMATIC BRAIN INJURY
Administration of the antioxidant enzyme SOD was
reported to have beneficial effects on survival and neuro-
logical recovery (Shohami et al. 1997a). The conjugation
of polyethylene glycol to SOD (PEG-SOD, Dismutec),
thereby improving BBB penetration and increasing
SOD’s plasma half-life, has been shown to reduce motor
deficits (Hamm et al. 1996). DeWitt et al. (1997) have

shown that PEG-SOD administration reverses cerebral
hypoperfusion after TBI in rats, and others have reported
that administration of lecithinized SOD (PC-SOD) re-
duced brain edema after weight-drop brain injury in rats
(Yunoki et al. 1997). A multicenter clinical trial of Dis-
mutec was conducted in the United States. Although ini-
tial Phase II studies were compelling (Muizelaar et al.
1993), the results of the larger Phase III trials in severely
head-injured patients were disappointing (Muizelaar et al.
1995; Young et al. 1996).
High-dose glucocorticoids stabilize membranes and
also reduce ROS-induced lipid peroxidative injury
(Braughler et al. 1987; Hall et al. 1987). Although many
early clinical studies reported that high-dose steroid
treatment is without effect in TBI (Braakman et al. 1983;
Cooper et al. 1979; Gudeman et al. 1979), a few tantaliz-
ingly positive studies have been published. Giannotta et
al. (1984) reported that high-dose methylprednisolone
significantly reduced mortality in severely head-injured
patients. In a multicenter trial conducted in Germany,
treatment of severely head-injured patients with the syn-
thetic corticosteroid triamcinolone significantly reduced
mortality and improved long-term neurological outcome
(Grumme et al. 1995). The CRASH (Corticosteroid Ran-
domization After Significant Head Injury) trial has been
designed to determine the effects of short-term steroid
treatment on death and disability after severe brain injury
in more than 7,000 patients in the United Kingdom
(Roberts 2001).
A group of 21-aminosteroid compounds have been

developed that lack true glucocorticoid activity while
maintaining the ability to scavenge ROS and inhibit lipid
peroxidation (Braughler and Pregenzer 1989). The most
widely evaluated member of this group of compounds, ti-
rilazad mesylate (Freedox), has been shown to enhance
neurological recovery and survival (Hall et al. 1988), at-
tenuate posttraumatic edema, reduce mortality (McIn-
tosh et al. 1992), improve motor function (Sanada et al.
1993), and increase metabolism of nonedematous tissue
adjacent to contusion (Hall et al. 1994) after experimental
TBI in rodents. Freedox appears to exert its antilipid per-
oxidative action through two mechanisms: free radical
scavenging and membrane stabilization (Fernandez et al.
1997; Kavanagh and Kam 2001). Treatment of TBI with
the Freedox-like 21-aminosteroid U-743896, or moder-
ate hypothermia, or a combination of both significantly
reduces axonal injury, although the 21-aminosteroid ther-
apy was more effective when treatment was initiated 40
minutes after injury (Knoblach et al. 1999). The lipophi-
licity of these 21-aminosteroids, coupled with their po-
tent inhibition of lipid peroxidation over a wide dose-
response range and the positive data collected from a wide
variety of animal models of CNS injury generated mo-
mentum to launch a multicenter clinical trial of Freedox
in the treatment of severely brain-injured patients in the
United States and Europe. However, the results of these
studies were largely negative (Marshall and Marshall
1995). Future studies enrolling patients with mild and
moderate severity of brain trauma may demonstrate clin-
ical use of this class of compounds.

An overproduction of the free radical nitric oxide (NO)
and its derivative anion peroxynitrite is also thought to play
an active role in the pathophysiology of TBI. Although
pharmacological intervention with both nonselective in-
hibitors of NOS and selective inhibitors of neuronal and
inducible NOS isoforms have proven effective in experi-
mental TBI (Gahm et al. 2002; Khaldi et al. 2002), further
preclinical work is necessary to clarify the therapeutic po-
tential of these compounds, particularly because NO can
be either neuroprotective or destructive, depending on its
spatiotemporal distribution and concentration. A novel
agent linking an antioxidant to a selective inhibitor of neu-
ronal NOS (BN 80933) has been shown to be neuroprotec-
tive in models of both TBI and cerebral ischemia (Chabrier
et al. 1999). The inhibition of NOS-induced cellular dam-
age may confer neuroprotection to the injured brain, and
future studies should emphasize the evaluation and devel-
opment of pathway-specific compounds.
Anti-Inflammatory Strategies
Although CNS inflammation was long believed to be a
catastrophic event leading to sustained functional impair-
ment and even death, there is increasing evidence that
inflammatory pathways may be of importance for initia-
tion of regenerative response. Posttraumatic edema for-
mation is associated with complex cytotoxic events and
vascular leakage after the breakdown of the BBB (Baskaya
et al. 1997; Unterberg et al. 1997), and a profound disrup-
tion of the BBB has been observed in a variety of experi-
mental TBI models (Barzo et al. 1996; Fukuda et al. 1995;
Soares et al. 1992) as well as in human TBI (Csuka et al.

1999; Morganti-Kossmann et al. 1999; Pleines et al.
1998). As such, infiltration and accumulation of polymor-
phonuclear leukocytes into brain parenchyma occurs in
the acute posttraumatic period, reaching a peak by 24
Pharmacotherapy of Prevention 709
hours postinjury (Soares et al. 1995; Stahel et al. 2000b).
Alterations in bloodborne immunocompetent cells have
been described in head-injured patients (Hoyt et al. 1990;
Piek et al. 1992; Quattrocchi et al. 1992). Immunocy-
tochemical studies have further demonstrated the pres-
ence of macrophages, natural killer cells, helper T cells,
and T cytotoxic suppressor cells as early as 2 days postin-
jury (Holmin et al. 1995). The entry of macrophages into
brain parenchyma has been shown to be maximal by 24–
48 hours after TBI in rats and humans (Holmin et al.
1995, 1998; Soares et al. 1995). A recent study of severe
TBI patients suggested that the activated cell population
after CNS trauma appears to be composed predominantly
of the macrophage/microglia lineage, as opposed to the
T-cell lineage (Lenzlinger et al. 2001). Both macrophages
and microglia have been proposed as key cellular ele-
ments in the progressive tissue necrosis—presumably
associated with the release of cytotoxic molecules that
may be involved in mediating the local inflammatory
response to trauma and the phagocytosis of debris from
dying cells—that occurs after CNS trauma (Morganti-
Kossmann et al. 2001).
Zhuang et al. (1993) have suggested a relationship be-
tween cortical polymorphonuclear leukocyte accumula-
tion and secondary brain injury, including lowered CBF,

increased edema, and elevated ICP. The migration of leu-
kocytes into damaged tissue typically requires the adhe-
sion of these cells to the endothelium, which is mediated
by the expression of the intercellular adhesion molecule-
1 (ICAM-1). An upregulation of ICAM-1 has been de-
scribed in a variety of experimental TBI models (Carlos et
al. 1997; Isaksson et al. 1997; Rancan et al. 2001), suggest-
ing a role for leukocyte adhesion in the pathobiology of
posttraumatic cell infiltration in the brain. In humans,
soluble ICAM-1 (sICAM-1) in CSF has been associated
with the breakdown of the BBB after severe TBI (Pleines
et al. 1998). However, treatment with the anti-ICAM-1
antibody 1A29 failed to significantly improve the learning
deficits or histopathological damage after severe TBI in
rats (Isaksson et al. 2001) (see Table 39–2). Recently, pros-
tacyclin, which is known to inhibit leukocyte adherence
and aggregation and platelet aggregation, was shown to
reduce neocortical neuronal death in rats after TBI
(Bentzer et al. 2001). Besides the expression of adhesion
molecules, leukocyte transmigration appears to require
the production of chemokines that activate and guide leu-
kocytes to the injured area.
The specific cytokines and growth factors that have
been implicated in the posttraumatic inflammatory cas-
cade include the interleukin (IL) and tumor necrosis fac-
tor (TNFα) families of peptides (for review see Allan and
Rothwell 2001). Alterations in systemic and intrathecal
concentrations of these cytokines have been reported to
occur in human patients after severe brain injury, and re-
gional mRNA and protein concentrations have been

shown to increase markedly in the acute posttraumatic
period after experimental brain trauma in the rat (Allan
and Rothwell 2001). IL-1α and IL-1β, two IL-1 agonists,
and IL-1 receptor antagonist (IL-1ra), a naturally occur-
ring physiological IL-1 antagonist, are produced as precur-
sors. While pro-IL-1α and pro-IL-1ra are active, pro-IL-1β
is activated when it is cleaved by IL-1 converting enzyme
(ICE or caspase-1). IL-1 has been implicated in an array
of pathological and nonpathological processes, including
apoptotic cell death (Friedlander et al. 1996), leukocyte–
endothelial adhesion (Bevilacqua et al. 1985), BBB dis-
ruption (Quagliarello et al. 1991), edema (Yamasaki et al.
1992), astrogliosis and neovascularization (Giulian et al.
1988), and synthesis of neurotrophic factors (DeKosky et
al. 1996). IL-1, in turn, stimulates other inflammatory
mediators, such as phospholipase A
2
, COX-2, prostaglan-
dins, NO, and matrix metalloproteinases (Basu et al.
2002; Rothwell and Luheshi 2000). A significant increase
in pro-IL-1β mRNA in the injured hemisphere as early as
1 hour and remaining up to 6 hours postinjury has been
reported after experimental TBI (Fan et al. 1995). A sim-
ilar acute increase in IL-1 activity and mature IL-1β pro-
tein levels after TBI has been reported (Taupin et al.
1993), which can be directly correlated to the severity of
injury in experimental models of TBI (Kinoshita et al.
2002).
Caspase-1 mRNA is increased in ipsilateral cortex and
hippocampus between 24 and 72 hours after TBI in rats

(Sullivan et al. 2002; Yakovlev et al. 1997) although in-
creased cleavage of caspase-1 is observed after human
brain injury (Clark et al. 1999). Intracerebroventricular
administration of IL-1ra results in improved cognitive
function without motor improvement (Sanderson et al.
1999), and administration of recombinant IL1-ra resulted
in reduced neuronal damage after TBI in rodents (Toul-
mond and Rothwell 1995). Despite the inability to readily
detect caspase-1 activity in the injured rat brain, adminis-
tration of a selective inhibitor of caspase-1 (e.g., acetyl-
Tyr-Val-Ala-Asp-chloromethyl-ketone [AcYVAD-cmk]
or the tetracycline derivative minocycline) before TBI
significantly reduces lesion volume and attenuates motor
deficits (Fink et al. 1999; Sanchez Mejia et al. 2001).
The pleiotropic cytokine IL-6 has been implicated in a
variety of physiological as well as pathological processes in-
cluding induction of nerve growth factor (NGF) expres-
sion (Frei et al. 1989; Gruol and Nelson 1997; Marz et al.
1999; Nieto-Sampedro et al. 1982). Elevated levels of IL-6
have been detected in the CSF and the serum of patients
with severe TBI over a period of up to 3 weeks after trauma
710 TEXTBOOK OF TRAUMATIC BRAIN INJURY
(Hans et al. 1999a; Kossmann et al. 1995). The higher con-
centration of IL-6 reported in the CSF of TBI patients
suggests an intrathecal production of this factor, which has
been reported to occur in several models of experimental
TBI (Woodroofe et al. 1991). Hans and coworkers (1999b)
demonstrated that IL-6 mRNA was upregulated in cortical
and thalamic neurons as well as in infiltrating macrophages
as early as 1 hour postinjury, whereas IL-6 immunoreactiv-

ity and protein levels in rat CSF peaked within the first 24
hours after TBI. In a study by Kossmann et al. (1996), a
temporal relationship between high CSF concentrations of
IL-6 and the detection of NGF in CSF was noted in brain-
injured patients. In vitro experiments using CSF from
these patients showed that IL-6 stimulated cultured pri-
mary mouse astrocytes to produce NGF, an effect which
could be significantly attenuated by preincubation with
anti-IL-6 antibodies (Kossmann et al. 1996). IL-6 released
in the CNS has also been shown to be associated with the
systemic acute phase response after severe TBI in humans
(Kossmann et al. 1995), indicating that centrally released
immune mediators may evoke a substantial systemic re-
sponse to trauma, with profound implications for the out-
come of TBI patients.
In a study subjecting IL-6 knockout mice and their
wild-type (WT) littermates to a cortical freeze lesion,
Penkowa and colleagues (1999) found that the lack of IL-
6 greatly reduced reactive astrogliosis and the appearance
of brain macrophages around the lesion site. IL-6 defi-
ciency also caused greater lesion-induced neuronal cell
loss. These observations highlight the dual role that this
pleiotropic cytokine may play in the posttraumatic cas-
cade. Conversely, a recent study using IL-6 knockout
mice subjected to TBI showed that these animals were
not significantly different from their WT littermates in
their response to TBI in several outcome measures, such
as neurologic motor function, BBB permeability, intrace-
rebral neutrophil infiltration, and neuronal cell loss (Sta-
hel et al. 2000b). Therefore, IL-6 appears to promote an

inflammatory response to trauma but at the same time
also seems to enhance neuronal survival. The exact na-
ture, severity, and type of the CNS injury as well as the
timing of IL-6 release may be decisive for either a detri-
mental or a beneficial effect of this factor after TBI.
IL-10 is an anti-inflammatory cytokine that inhibits a
variety of macrophage responses and is also a potent sup-
pressor of T-cell proliferation and cytokine response by
blocking expression of TNF and IL-1 (Benveniste et al.
1995; Chao et al. 1995) and enhancing synthesis and se-
cretion of their endogenous antagonists (Cassatella et al.
1994; Joyce et al. 1994). IL-10 also reduces leukocyte–
endothelial interactions that promote procoagulation
(Jungi et al. 1994) and extravasation of blood cells (Krakauer
1995; Perretti et al. 1995). Subcutaneous or intravenous
administration of IL-10 before or after TBI in rats signif-
icantly reduced TNF expression in the injured cortex and
enhanced neurological recovery (Knoblach and Faden
1998). Although a combination of IL-10 systemic admin-
istration and hypothermia was expected to exhibit in-
creased neuroprotection after TBI, this combination
therapy resulted in adverse effects when compared with
hypothermia alone after TBI (Kline et al. 2002).
TNF-α, a proinflammatory cytokine with cytotoxic
properties, has been detected in the CSF and the serum of
patients with TBI (Goodman et al. 1990; Ross et al.
1994). Csuka and coworkers (1999) found increased pat-
terns of TNF-α concentrations among 28 TBI patients
over a 3-week study period. These observations together
with the detection of TNF-α mRNA and protein in the

injured rodent brain suggest that this cytokine is mark-
edly and acutely unregulated in brain tissue after TBI
(Fan et al. 1996; Shohami et al. 1994). Increases in TNF-
α expression were immunohistochemically localized
primarily to neurons and to a much lesser extent to astro-
cytes after TBI in rats (Knoblach et al. 1999). The upreg-
ulation of TNF-α therefore appears to be an endogenous
response of the brain parenchyma to trauma, as opposed
to being the result of a nonspecific invasion of the brain
by peripheral blood leukocytes. TNF-α may mediate sec-
ondary damage after TBI through several different mech-
anisms (for a review see Shohami et al. 1999). This cyto-
kine is known to affect BBB integrity, leading to cerebral
edema and infiltration of blood leukocytes, and it has
been shown to induce expression of the receptor for the
potent secondary inflammatory mediator anaphylatoxin
(or C5a) on neurons (Stahel et al. 2000a). Furthermore,
TNF can induce both apoptosis and necrosis via intracell-
ular signaling pathways (Reid et al. 1989).
On the basis of the above evidence, it is not surprising
that both direct and indirect inhibition of TNF-α activity
has been shown to be beneficial in experimental TBI
studies. Administration of the immunosuppressive pen-
toxifylline as well as of TNF-α binding protein, a physio-
logical inhibitor of TNF-α activity, has been shown to
significantly diminish edema formation and enhance mo-
tor function recovery after experimental TBI (Shohami et
al. 1996). These studies suggest a detrimental effect of
TNF-α in the sequelae of TBI. However, more recent in-
vestigations in genetically engineered animals point again

toward a dual role of this cytokine after TBI. Mice defi-
cient in both subtypes of TNF receptors have been shown
to be more vulnerable to TBI than WT animals, suggest-
ing a neuroprotective role for TNF-α in the pathological
sequelae of brain injury (Sullivan et al. 1999). Moreover,
brain-injured TNF-deficient (–/–) mice show an early
Pharmacotherapy of Prevention 711
benefit from the lack of TNF, with neurologic motor
scores initially better than brain-injured WT controls.
However, this trend is reversed from 1–4 weeks after in-
jury: the injured WT animals recover while the TNF –/–
mice do not (Scherbel et al. 1999). Taken together, these
data suggest that a differential role of this cytokine may be
dependent on the temporal profile of its release within the
posttraumatic cytokine cascade. These data suggest that
antagonism of TNF activity may be beneficial for the in-
jured brain in the acute posttraumatic period but may
prove deleterious if extended into the chronic phase,
when it may be essential for initiating a regenerative re-
sponse. Alternatively, another possibility allows that the
expression of TNF receptor subtypes may change over
the acute and chronic postinjury phases, and recent evi-
dence suggests that neuronal death or survival in response
to TNF-α may depend on the particular subtype that is
predominantly expressed (Yang et al. 2002).
The role of the kallikrein–kinin system in inflamma-
tion and pain has led to the development of bradykinin B
2
receptor antagonists. In a multicenter clinical trial,
Bradycor (CP-0127) was found to be neuroprotective in

severely brain-injured patients (Marmarou et al. 1999),
and a recently developed nonpeptide B
2
receptor antago-
nist (LF-16–0687Ms) was shown to reduce TBI-induced
brain vasogenic edema in rats (Stover et al. 2000b). Inhi-
bition of the posttraumatic inflammatory cascade contin-
ues to be a viable avenue of development of neuroprotec-
tive compounds.
Recently, several groups have implicated modulation
of the endocannabinoid system, including the arachi-
donoylethanolamide (anandamide), 2-arachidonyl glyc-
eryl ether, and 2-arachidonoyl glycerol (2-AG) ligands
and their cognate CB
1
and CB
2
receptors, as a possible
therapeutic paradigm after TBI. Cannabinoid receptor
agonists have been shown to inhibit glutamatergic synap-
tic transmission (Shen et al. 1996) and protect neurons
from excitotoxicity in vitro (Shen and Thayer 1998). It
has also been suggested that cannabinoid receptor ago-
nists can counteract the vasoconstrictory effects of endo-
thelin-1 (Chen and Buck 2000), a molecule that may play
a role in TBI-induced ischemia. Gallily et al. (2000) have
reported that 2-AG suppresses formation of ROS and
have noted lower levels of TNF-α in the serum of LPS-
treated mice after administration of 2-AG (Gallily et al.
2000). Most recently, it has been demonstrated that levels

of anandamide (Hansen et al. 2001; Panikashvili et al.
2001) and 2-AG (Panikashvili et al. 2001) are significantly
elevated after TBI, and if this response is further aug-
mented by administration of synthetic 2-AG, injured an-
imals exhibit a significant reduction in brain edema, re-
duced lesion volume, and quicker recovery of neurological
function (Panikashvili et al. 2001). Collectively, these data
provide a rationale for the use of cannabinoids in the
treatment of TBI. Indeed, dexanabinol (HU-211), a non-
psychotropic cannabinoid, has been reported to have a
significant neuroprotective role after TBI. In a random-
ized, placebo-controlled Phase II clinical trial, patients
with severe closed head injury receiving an intravenous
injection of dexanabinol showed significantly better ICP,
cerebral perfusion pressure, and clinical outcome (Knol-
ler et al. 2002).
Neurotrophic Factors
The peptide growth factors, including NGF, basic fibro-
blast growth factor (bFGF), ciliary neurotrophic factor
(CNTF), brain-derived neurotrophic factor (BDNF), in-
sulinlike growth factor (IGF-1), neurotrophin-3 (NT-3),
neurotrophin-4/5 (NT-4/5), and glial-derived neu-
rotrophic factor (GDNF), all function in the normal
brain to support neuronal survival, induce sprouting of
neurites (neuronal plasticity), and facilitate the guidance
of neurons to their proper target sites during develop-
ment (for a review see Huang and Reichardt 2001) (Fig-
ure 39–3). Several recent studies suggest that some of
these neurotrophic factors are altered after brain injury,
perhaps as a response designed to facilitate neuronal re-

pair and reestablish functional connections in the injured
brain. DeKosky and colleagues (1994) observed a marked
increase in NGF mRNA and protein expression in the
acute posttraumatic period after both weight-drop and
TBI in rats, whereas a significant reduction in NGF
p75
NTR
receptor was observed in the chronic postinjury
period after TBI in rats (Leonard et al. 1994). Goss et al.
(1997) observed an increase in the antioxidant enzyme
glutathione peroxidase and catalase concentrations over a
time course that reflected the temporal increase in NGF
and hypothesized that the upregulation of NGF after TBI
serves as a mediator of oxidative homeostasis by inducing
the production of ROS. The same authors suggested that
astrocytes are the major source of NGF upregulation af-
ter TBI in the rat (Goss et al. 1998). Using models of TBI,
several laboratories reported that intraparenchymal ad-
ministration of NGF can attenuate cognitive but not neu-
robehavioral motor deficits or hippocampal cell loss after
TBI in rats (Dixon et al. 1997; Sinson et al. 1995, 1996)
(see Table 39–2). Follow-up studies demonstrated that
central NGF administration can reduce the extent of apo-
ptotic cell death in septal cholinergic neurons after TBI
(Sinson et al. 1997) and can reverse the trauma-induced re-
ductions in scopolamine-evoked acetylcholine release
(Dixon et al. 1997). Recently, both rat- and hippocampal-
712 TEXTBOOK OF TRAUMATIC BRAIN INJURY
derived precursor (HiB5) cells and human NT2M neu-
rons, transfected to express NGF and transplanted into the

injured cortex, have been shown to improve cognitive and
neurological motor function and reduce CA3 neuronal cell
death when transplanted into the injured cortex at 24 hours
after TBI in rats (Longhi et al., in press; Philips et al. 2001).
BDNF, a member of the neurotrophin family of
trophic factors, has almost 50% homology with NGF
(Leibrock et al. 1989), although BDNF is more abundant
in the adult brain than NGF (Maisonpierre et al. 1990).
BDNF has two receptors: the high-affinity receptor TrkB
and the low-affinity receptor p75
NTR
(Table 39–3). A sec-
ond ligand, NT-4/5, also binds to TrkB with high affinity
and is expressed ubiquitously within the adult rodent
brain (Timmusk et al. 1993); however, changes in NT-
4/5 expression have not been evaluated to date in an ex-
perimental model of TBI, nor has its therapeutic value af-
ter TBI been evaluated and documented. BDNF and its
primary receptor, the TrkB tyrosine kinase, are found in
many areas of the brain, including the hippocampal CA3
and the dentate hilus regions (Nawa et al. 1995; Yan et al.
1997a, 1997b) (see Table 39–3). BDNF regulates the gen-
eration and differentiation of neurons during develop-
ment, axon growth and growth cone mobility, and synap-
tic plasticity (Lu and Chow 1999; McAllister et al. 1999;
Schinder and Poo 2000), and it was recently shown to
promote neurogenesis from adult stem cells in vivo (Ben-
raiss et al. 2001; Pencea et al. 2001).
Initial observations suggested that a rapid increase in
BDNF mRNA levels occurs in injured brain as early as 1

FIGURE 39–3. Growth factors and their cognate receptors.
BDNF = brain-derived neurotrophic factor; bFGF = basic fibroblast growth factor; FGFR = FGF receptor; GDNF = glial-derived
neurotrophic factor; GFR = GDNF family receptor; IGF = insulin-like growth factor; IGFBR= IGF receptor; NGF = nerve growth
factor; NT-3 = neurotrophin-3; VEGF = vascular endothelial growth factor.
Pharmacotherapy of Prevention 713
hour after TBI and persists for days (Griesbach et al.
2002; Hicks et al. 1997; Oyesiku et al. 1999; Truettner et
al. 1999) with a concomitant acute increase in trkB
mRNA levels within the hippocampus (Hicks et al. 1998;
Mudo et al. 1993). Animals in which milder injuries are
induced exhibit unilateral, rather than bilateral, increases
in BDNF and trkB mRNA levels (Hicks et al. 1999b).
Another study reported significantly decreased levels of
BDNF mRNA in the injured cortex at 72 hours and in-
creased levels in other adjacent cortical areas from 3–24
hours postinjury (Hicks et al. 1999a). This apparent dis-
crepancy in observations could be a function of differ-
ence of injury models, the time points chosen for obser-
vation if expression levels prove to be biphasic, or
differences in the sensitivity of assays used to measure the
reported changes. In one of the few treatment studies,
administration of BDNF directly into injured brain pa-
renchyma failed to attenuate behavioral deficits or histo-
logical damage after TBI in rats (Blaha et al. 2000). Al-
though there are many possible explanations of why
BDNF administration failed to confer neuroprotection
after TBI, one interesting possibility is that injury selec-
tively upregulated the truncated form of trkB rather than
the full-length form.
The neurotrophic factors GDNF, neurturin, per-

sephin, and artemin are included among the TGF-β super-
family (for a review see Airaksinen et al. 1999) (see Table
39–3). The GDNF family ligands signal via a two-compo-
nent receptor complex that includes c-Ret, a protoonco-
gene and tyrosine kinase receptor (Durbec et al. 1996;
Trupp et al. 1996), and GDNF family receptor-α (GFR-
α), a glycosyl-phosphatidylinositol-anchored protein that
is devoid of an associated kinase activity (Baloh et al. 1997;
Jing et al. 1996) (see Table 39–3). The GDNF transcript
has been detected in all major brain regions (Schaar et al.
1993), including those regions vulnerable to TBI, and
GDNF and neurturin exert neurotrophic effects in a wide
spectrum of neuronal populations (Arenas et al. 1995;
Henderson et al. 1994; Kotzbauer et al. 1996; Lin et al.
1993; Mount et al. 1995). GDNF appears to reduce
NMDA-induced calcium influx via the activation of the
mitogen-activated protein kinase pathway and as a result
attenuates NMDA-induced excitotoxic cell death (Nicole
et al. 2001). Such activity suggests that GDNF may be an
especially attractive candidate for reducing excitotoxic
neuronal death after TBI if administered at acute time
points when excitotoxicity is predominant (see above).
To date, little evidence exists documenting changes in
expression of GDNF or its receptors after TBI. A single
preliminary report suggests that GDNF protein levels, as
measured by quantitative enzyme-linked immunosorbent
assay (ELISA), increase approximately 2.5 times in the in-
jured cortex after TBI in rats (Shimizu et al. 2002). When
GDNF or artificial CSF is infused continuously for 7 days
into the lateral ventricle after TBI in rats, a significant de-

crease was observed in injury-induced CA2 and CA3 cell
loss (Kim et al. 2001). Likewise, when an adenovirus engi-
neered to confer GDNF expression was injected into the
sensorimotor cortex 24 hours before freeze-lesion injury in
rats, a significant reduction in lesion volume and the num-
ber of cells immunopositive for iNOS, activated caspase-3,
and TUNEL was observed (Hermann et al. 2001).
The polypeptide FGF-2 (also known as bFGF) is a
member of the FGF family, which currently includes seven
members (for a review see Gimenez-Gallego and Cuevas
1994), all of which possess the ability to stimulate fibroblast
growth with the notable exception of FGF-7. FGF-2 binds
to four cell surface receptors that are expressed as a number
of splice variants (for a review see Nugent and Iozzo 2000),
of which FGFR1 is the high-affinity receptor (for a review
see (Stachowiak et al. 1997) (see Table 39–3). FGF-2 and
FGFR1 proteins, as well as their mRNAs, have been dem-
onstrated to be expressed in both the developing and the
adult brain (for a review see Unsicker et al. 1991). FGF-2
has been implicated as a neurotrophin, a neurite branching
factor, an enhancer of synaptic transmission, and a neural
inducer (Abe and Saito 2001).
Initial reports demonstrated an increase in FGF-2
protein after TBI at the lesion periphery in cells with
morphological features consistent with reactive astro-
cytes (Finklestein et al. 1988). Further analysis resulted
in the observation that FGF-2 mRNA, FGF-2 protein,
FGFR1 mRNA, and FGFR1 protein were increased as
TABLE 39–3. Neurotrophic receptor families and
endogenous ligands in the central nervous system

Types of receptors
and neurotrophic
factor family
Neurotrophic factors as
ligand
Tyrosine kinase receptors —
NGF receptor family Neurotrophins (NGF, BDNF,
NT-3, NT-4/5)
FGF receptor family FGF-2
Ret receptor family GDNF, neurturin, artemin,
persephin
Insulin receptor family Insulin, IGF-1
VEGF receptor family —
Note. BDNF=brain-derived neurotrophic factor; FGF=fibroblast growth
factor; GDNF=glial cell-line–derived neurotrophic factor; IGF=insulin-
like growth factor; NGF=nerve growth factor; NT-3=neurotrophin 3; NT-
4/5= neurotrophin 4/5; VEGF=vascular endothelial growth factor.
714 TEXTBOOK OF TRAUMATIC BRAIN INJURY
early as hours postinjury and persisted for at least 2 weeks
postinjury (Frank and Ragel 1995; Reilly and Kumari
1996; Yang and Cui 1998). Furthermore, at acute time
points, FGF-2 co-localized with MAC-1 immunoposi-
tive microglial/macrophages, whereas at later time
points FGF-2 co-localized with reactive astrocytes
(Frautschy et al. 1991; Reilly and Kumari 1996), neurons,
and vascular endothelial cells (Logan et al. 1992; Yang
and Cui 1998). Given the early expression patterns and
the localization of the FGF-2 ligand and its receptors,
these data collectively suggest that one of the roles of
FGF-2 induction after TBI may be in stimulating astro-

gliosis. Additionally, recent evidence suggests that FGF-
2 is necessary and sufficient to stimulate proliferation and
differentiation of neuroprogenitor cells in the adult hip-
pocampus after various brain insults (Yoshimura et al.
2001) and may regulate postlesional sprouting (Ramirez
et al. 1999). Dietrich et al. (1996) reported that acute ad-
ministration of FGF-2 could attenuate cortical cell loss
after TBI in rats, whereas McDermott et al. (1997) dem-
onstrated that delayed intraparenchymal administration
of FGF-2, beginning 24 hours after TBI, can signifi-
cantly improve posttraumatic cognitive deficits in the rat.
Exogenous FGF-2 was also shown to reduce hippocam-
pal cell death after diffuse brain injury (Yang and Cui
2000). Furthermore, the combination of FGF with hypo-
thermia (Yan et al. 2000) may increase the magnitude of
the protective effect.
IGF-I is polypeptide hormone that shares several
structural features with insulin (Isaksson et al. 1991) and
is produced in many tissues in the body including the
brain (Bondy and Lee 1993; Rotwein et al. 1988; Werther
et al. 1990). In rodents, expression of mRNA for IGF-I is
highest during the development of the nervous system,
but it is also expressed in many regions of the adult rat
brain (Bondy and Lee 1993). IGF-I readily crosses the
BBB and as a result the brain is influenced by the concen-
tration of circulating IGF-I (Armstrong et al. 2000; Carro
et al. 2000; Pulford and Ishii 2001). IGF-I exerts its ac-
tions primarily via the type I IGF receptor, although in-
teractions with the insulin receptor have been reported
(Butler et al. 1998; Lamothe et al. 1998) (see Table 39–3).

IGF binding proteins (IGFBPs) modulate the interaction
of IGF-I with its receptor (Ocrant et al. 1990). IGFBP-2,
IGFBP-4, and IGFBP-5 are the predominant binding
proteins in the brain and can bind IGF-I, thus rendering
it biologically inactive (Dore et al. 2000). However, there
is also evidence suggesting that some IGFBPs potentiate
the effect of IGF-I, possibly by presenting IGF-I more ef-
ficiently to its receptor, protecting IGF-I from degrada-
tion, or transporting IGF-I to regions of injury (Beilharz
et al. 1998; Guan et al. 2000).
Initial reports of IGF-I expression after TBI local-
ized expression to reactive astrocytes from acute time
points to 1 month after injury (Garcia-Estrada et al.
1992). In a different model of TBI, a dramatic increase
in the expression of IGFBP-2 and IGFBP-4 mRNA
was observed between 24 hours and 7 days within in-
jured cortex, whereas increased expression of IGF-1
mRNA peaked at 3 days postinjury (Sandberg Nor-
dqvist et al. 1996). This increase in IGFBP-4 mRNA is
completely blocked by administration of the NMDA an-
tagonist MK-801, and injury-induced IGF-1 mRNA ex-
pression is blocked by both MK-801 and the AMPA an-
tagonist CNQX (Nordqvist et al. 1997), suggesting
that activation of glutamatergic systems may influence
IGF expression or function in the setting of brain in-
jury. In contrast, another study provided evidence that
MK-801 reversed a measured decrease in IGF-II
mRNA levels after injury (Giannakopoulou et al.
2000). Further studies using IGFBP-1 overexpressing
transgenic mice observed that reactive astrogliosis, re-

flected by morphology and glial fibrillary acidic protein
expression in astrocytes in response to a mechanical le-
sion, was substantially less in transgenic compared with
WT mice (Ni et al. 1997), suggesting that IGF-I may
play a role in astrogliosis.
Saatman and colleagues (1997) showed that continu-
ous subcutaneous administration of IGF-I for 7 days
dramatically accelerated neurological motor recovery
and attenuated cognitive deficits after TBI in rats. A
Phase II clinical trial demonstrated that continuous in-
travenous IGF-I in moderate to severe TBI patients re-
sulted in greater weight gain, higher glucose concentra-
tions and nitrogen outputs, and moderate to good
Glasgow Outcome Scale scores at 6 months (Hatton et
al. 1997). Taken together, the above data suggest that
systemic IGF-I therapy should be further evaluated as a
potential candidate for neuroprotection after clinical
brain injury.
The VEGF family currently includes six known
members. VEGF, or VEGF-A as it is now designated,
was the first member of the VEGF family to be discov-
ered and is also the best-characterized member (for a
review see Neufeld et al. 1999). VEGF-A is established
as a major inducer of endothelial cell proliferation, mi-
gration, sprouting, neural tube formation, and perme-
ability during embryonic vasculogenesis and in physio-
logical and pathological angiogenesis. These effects are
mediated mainly by the VEGF receptor VEGFR-2 (see
Table 39–3). More recently, VEGFR-1 was suggested
to be an important mediator of stem cell recruitment

(Eriksson and Alitalo 2002; Jin et al. 2002). A role of
VEGF in BBB breakdown and angiogenesis/repair has
727
40
Prevention
Elie Elovic, M.D.
Ross Zafonte, D.O.
PREVENTABLE INJURY IS one of the most signifi-
cant health care issues in the United States. Estimates
place the annual cost in the United States to be $260 bil-
lion, and 30% of all life years lost before age 75 years are
a result of injury. The Centers for Disease Control and
Prevention (CDC) estimates that during 1995, 2.6 mil-
lion hospital discharges and more than 36 million emer-
gency department visits occurred as a result of injury
(Centers for Disease Control and Prevention 2001). At
the more serious end of the spectrum, injury is the cause
of 150,000 deaths every year and is the leading source of
death for Americans ages 1–44 years (Nguyen et al. 2001).
Looking specifically at traumatic brain injury (TBI),
the figures are only slightly less daunting, with TBI one of
the leading causes of death and disability for children and
young adults in the United States. The CDC estimates
that in the United States between 1 million and 1.5 million
people seek medical attention secondary to TBI. In addi-
tion, there are 230,000 hospitalizations and 80,000–
90,000 people who develop disability secondary to TBI
every year (Centers for Disease Control and Prevention
2001; McDeavitt 2001; Thurman et al. 1999). TBI also ac-
counts for more than 50,000 deaths annually, which con-

stitutes one-third of all injury-related deaths. Current es-
timates place the number of Americans who have some
disability as a result of TBI at roughly 5.3 million (Centers
for Disease Control and Prevention 2001). Schootman
and Fuortes (2000) reported that during the years 1994–
1997, 1.4 million people in the United States sought care
either at a doctor’s office or the emergency department
secondary to TBI, whereas Guerro et al. (2000) reported
TBI incidence between 392 and 444 per 100,000 popula-
tion when emergency department visits are included.
These numbers suggest a much higher incidence of TBI
than those based on deaths and hospital admissions.
Looking at deaths and hospital admissions, TBI inci-
dence is close to 100 per 100,000 (Thurman et al. 1999).
This is a drop of 50% from previous reports of rates of 200
per 100,000 during the 1970s and 1980s (Annegers et al.
1980; Centers for Disease Control and Prevention 2001;
Jagger et al. 1984; Kraus et al. 1984). The decrease may in
part be a result of insurance’s influence on admission deci-
sions, in addition to prevention efforts. This is in contrast
to TBI mortality, because a reduction in the incidence is
more likely a result of prevention efforts. In 1980, the rate
of TBI-related mortality in the United States was 24.7 per
100,000. This had fallen 20% by 1994 to a rate of 19.8.
Motor vehicle–related mortality showed the greatest de-
cline. With the advent of air bags, seat belts, and child
safety seats, mortality dropped 38% from 11.1 to 6.9 per
100,000 between 1980 and 1994 (Thurman et al. 1999).
TBI Versus Other Disabling Conditions
TBI has often been called the silent or invisible epidemic

(Centers for Disease Control and Prevention 2001), the
stepchild that has only received minimal public awareness
and dedication of financial resources to its treatment and
prevention. To obtain a better perspective on this state-
ment, one can compare TBI incidence to other conditions
that have greater notoriety despite a lower incidence. The
Brain Injury Association of America has made substantial
effort to spread the word and inform the lay and scientific
public about TBI incidence. The association has a Web site
that actively deals with the issue (Brain Injury Association
of America 2001b). At this time, the annual incidence of
TBI is greater than that of the more widely known condi-
tions of spinal cord injury, breast cancer, multiple sclerosis,
and human immunodeficiency virus (HIV) (Figure 40–1).
728 TEXTBOOK OF TRAUMATIC BRAIN INJURY
The magnitude of TBI-related mortality as compared
with these other conditions is quite striking. As compared
with the 50,000 deaths that occur each year as a result of
TBI, the number of HIV-related deaths during 1999 was
16,273 (U.S. Department of Health and Human Services
2001), whereas 43,700 people died during 1999 from
breast cancer (American Cancer Society 2001). What may
be most striking for HIV information is that the mortality
rate in 1999 is a substantial drop from the 1995 high of
50,610 HIV-related deaths (U.S. Department of Health
and Human Services 2001). With dedication to preven-
tion, treatment, and increased public awareness, a similar
drop in the personal suffering and economic loss of TBI
may also be possible.
Economics of TBI and Its Prevention

Because TBI often occurs in the very young, the cost to
society in lost years of productivity and years of dependent
care can be enormous. Estimates of work years lost because
of TBI run as high as 2.6 million, which accounts for 58%
of all injury-related losses reported (McDeavitt 2001). Max
et al. (1991) reported that the cost associated with TBI in
1988 dollars was $44 billion. With the enormous personal
suffering, loss of life, and economic hardship on society, the
fact that many of these often catastrophic events are pre-
ventable only compounds this tragedy.
With the competition for dollars in today’s world, the
cost-benefit ratio of preventive efforts is an issue of some
importance. Some prevention techniques are widely ac-
cepted in society today, such as childhood vaccinations and
flu vaccine, as they have proven to be efficacious both fi-
nancially and as a vehicle for health maintenance. This has
been proven to be true with injury prevention as well. Pe-
diatricians who administer injury prevention counseling to
families with children younger than 4 years have demon-
strated a 13 to 1 benefit to cost ratio (Miller and Galbraith
1995). Bicycle helmets for children ages 4–15 years have
also shown great benefit. For every $1 spent on bicycle hel-
mets, society saves $2 in direct medical costs, $6 in future
earnings, and $17 in quality of life. The use of child safety
seats for children younger than 4 years has also proven to
be of substantial benefit to society. If child safety seats are
used, the savings in direct medical costs, future earnings,
and quality of life are $2, $6, and $25, respectively (Miller
et al. 2000). Finally, Graham et al. (1997) demonstrated
that the use of seat belts and air bags demonstrated a cost

effectiveness that matched any other prevention effort that
addressed any medical or public health issues.
What Is Prevention?
People use the word prevention for many activities. Speed
limits, highway barriers, and highway designs to lessen the
number of motor vehicle accidents (MVAs) are clearly aimed
at injury prevention. So too are seat belts and air bags, for
though they do not play a major role in accident prevention,
they minimize personal injury to passengers in the car once
an accident occurs. The development of advanced trauma
care to mitigate further injury is also a form of prevention.
Although all three of these examples are geared toward
injury prevention, they clearly have differences. As a result,
the distinction between primary, secondary, and tertiary pre-
vention has been made. Primary prevention efforts are
directed to prevent the injury from occurring. Other exam-
ples of primary prevention include fall-proofing homes, traf-
fic laws and their enforcement, salting of ice-covered roads,
and education about drinking and driving. In contrast, sec-
ondary efforts lessen an injury’s effect once it has occurred,
with helmets, automobile design, and air bags examples of
secondary prevention. Development of advanced trauma
care and emergency management services are examples of
tertiary prevention (Nguyen et al. 2001).
Injury Control Theory
Originally, the general belief was that TBI was a result of
accidents, which implied that all persons had equal prob-
ability of sustaining injury (Elovic and Antoinette 1996;
FIGURE 40–1. A comparison of traumatic brain
injury and leading injuries or diseases: annual

incidence.
AIDS=acquired immunodeficiency syndrome; HIV=human im-
munodeficiency virus.
Source. Brain Injury Association of America, March 2001.
Available at: />2002.Fact.Sheet.tbi.incidence.pdf. Accessed March 22, 2004.
Used with permission.
Traumatic
brain injuries
1,500,000
Breast
cancer
176,300
HIV/AIDS
43,681
Spinal cord
injuries
11,000
Multiple
sclerosis
10,400
1,500,000
1,000,000
500,000
100,000
10,000
2,000,000
Annual incidence
Prevention 729
Guyer and Gallagher 1985). Any discussion of TBI epide-
miology, such as the one in Chapter 1, Epidemiology,

clearly demonstrates the fallacy of this position. There are
certain people who are at higher risk of sustaining injury.
As a result, there has been substantial work devoted to the
identification of people at risk and to developing effective
preventive countermeasures (Elovic et al. 1996; Teutsch
1992), with a substantial increase in the science of injury
control theory since the 1950s.
The relationship between infectious pathogens and
their related illness has been investigated since the time of
Louis Pasteur, more than 100 years ago. More than 50
years ago, Gordon first raised the idea that injury can be
studied in the same fashion as infectious illness (Gielen
and Girasek 2001). In 1961, James Gibson introduced the
idea that the energy that induced injury could be studied
as a causative agent similar to an infectious agent (Gielen
and Girasek 2001). Baker (1975) compared the concept of
the epidemiologic model of injury to that of illness by de-
scribing the etiologic agent as one that demonstrates a
negative effect on a host in a particular environment.
Haddon Matrix
Further work on the study of injury prevention was carried
out by Haddon, resulting in the construction of the Haddon
Matrix (Haddon 1968). With this model, injury is divided
into three separate areas. First is the host; the second is the
vector, or injuring agent; and the third is the environment
that the first two interact within. The environment is further
divided into two separate components, physical and social.
In addition, the matrix model divides the injury using tem-
poral factors; preinjury, injury, and postinjury. This is com-
parable to the primary, secondary, and tertiary prevention

efforts mentioned in the section What Is Prevention?
(Nguyen et al. 2001). Using these sets of variables, a table
can be created in which each cell represents an area and a
temporal component. All factors related to injury can be
placed into one of the table’s cells. An example of this would
be the decreased balance and vision of an elderly person who
sustained a fall. In the Haddon Matrix, these items would be
placed in the host, preinjury cell. The contribution of the
shag rug that caused the fall would be classified as preinjury,
physical environment. The vector in falls is the energy that
is transmitted to the brain tissue. Head height is a source of
potential injury before an event. Clearly, by standing on a
ladder there is greater potential energy, which places the
host at greater risk. The energy is converted to kinetic
energy during a fall that is transmitted to the brain tissue at
impact. The distortion of brain tissue and bleeding that
result from the energy transfer can be considered the postin-
jury vector component.
Passive Versus Active Strategies
There are two general approaches to the promotion of
injury prevention, passive and active. A passive strategy is
one that the host takes no action to use (Gielen et al.
2001) and may as a result be more effective than active
interventions. By nature, passive strategies offer protec-
tion to a larger percentage of the population (Karlson
1992). Some examples of these include air bags, road bar-
riers, fingerprint-based gun locks, and car safety engi-
neering. A system that would not let a driver start his or
her car if he or she could not pass a Breathalyzer test is
another example of a passive strategy that would prevent

the host from driving while intoxicated. Active strategies
are ones that require some action on the host’s part. The
donning of a seat belt, avoiding driving when under the
influence, motorcycle helmet usage, and car seats are just
some examples of active prevention. Although these items
may be more effective than passive approaches, their dis-
tinct disadvantage is that somehow society must convince
the host to use them.
As a result, there is some controversy as to how injury
prevention resources should be applied. It is general
knowledge that changing human behavior is a challeng-
ing endeavor, and passive interventions aimed at the vec-
tor and environment may be the most effective in reduc-
ing death and injury (Haddon 1970). That does not
negate the potential benefit of using a combined ap-
proach, because the use of one method does not exclude
the use of another. An example of this is, of course, the use
of seat belts in combination with air bags. Each preven-
tion method has shown its benefit; however, using both
together has been shown to be more effective than either
one by itself. As a result, there is evidence that a combined
approach of active and passive interventions should be
used in a comprehensive approach.
Facilitating Active Strategies to
Develop Comprehensive Injury Control
How can society develop a comprehensive approach to
injury control? Also, how can society influence the host
that can be potentially injured to act according to its
wishes? These important questions must be answered to
maximize the benefit of an injury control program.

The first of these questions can only be answered once
one defines what components are critical to the develop-
ment of a comprehensive program. Clearly, engineering
solutions are important components of passive interven-
tions such as energy-absorbing car bodies, road barriers,
and air bags. What methods should be used for the active
730 TEXTBOOK OF TRAUMATIC BRAIN INJURY
strategies? Education is an important component, both at
the individual and community level (Nguyen et al. 2001).
However, there is a problem if education is performed
alone without giving the listener some incentive to
change his or her behavior on the basis of the information
presented. An example of this was the early public service
announcements that used fear as a potential motivator for
increased seat belt usage, but they were largely ineffective
(Roberston et al. 1974). Education prevention counseling
by health care professionals in a clinical setting has been
proven to be much more effective. DiGuiseppi and Rob-
erts (2000), after reviewing many clinical trials, reported
that education counseling was effective in encouraging
the use of automobile restraints.
A method to facilitate a host’s compliance with safer
behaviors is to connect them to incentives. This can be
accomplished with legislative intervention and appropri-
ate enforcement. Community-based intervention pro-
grams combining education with legislative options has
been shown to be effective in increasing bicycle helmet
usage (Klassen et al. 2000). Work performed in three sep-
arate Maryland counties explored the issue of children’s
bicycle helmet usage under three separate conditions. In

one county, legislation and education were undertaken,
and helmet use increased from 4% to 47%. Another
county used education alone and experienced a small, sta-
tistically insignificant increase in usage from 8% to 19%.
The third county, which did nothing, actually demon-
strated a decreased rate of helmet usage from 19% to 4%.
The third piece of the puzzle to facilitate active inter-
ventions is enforcement of legislation. Passing laws with-
out proper enforcement leads to only minimal benefits,
with seat belts being an example. By 1984, all passenger
cars were required to have seat belts. However, rates of
usage were only 15%. This rate increased to 42% by 1987
with a combination of educative efforts and seat belt leg-
islation. By 1992, when secondary enforcement laws were
enacted for nonuse of seat belts, usage increased to 62%.
A secondary enforcement law is one that allows the giving
of a citation when the driver has been pulled over for an-
other traffic offense. This 62% usage rate persisted
through 1998 in the states that used secondary enforce-
ment laws. In states that have enacted primary enforce-
ment legislation, which allowed ticketing when seat belt
nonuse was the only infraction, usage rates increased to
79% (National Highway Traffic Safety Administration
1999). In summary, facilitation of active prevention re-
quires a combination approach. Education, both at a
community and individual level, must be included with
appropriate legislation and its enforcement. Standing in
the way of many of these changes is the idea that preven-
tive legislation infringes on personal freedoms. The op-
position to gun control by the National Rifle Association

and to helmet laws by motorcycle clubs are just two exam-
ples of this problem. However, with the great cost to so-
ciety, both financially and emotionally, of TBI the gov-
ernment has not only the right, but also the obligation, to
deal effectively with these issues.
TBI Prevention and Motor Vehicles
As the discussion is turned to more specific issues of TBI
prevention, it is appropriate to begin with efforts that
involve motor vehicles. The reasons for this are twofold.
First, MVAs are the leading cause of TBI in the United
States (Centers for Disease Control and Prevention
2001), with data from state registries reporting that trans-
portation accounted for 48.9% of TBIs reported (Thur-
man et al. 1999). Second, there is evidence that preven-
tion efforts aimed at reduction of transportation-related
mortality have been efficacious. There was a 38%
decrease in motor vehicle–related deaths from 1980 to
1994 (Centers for Disease Control and Prevention 2001).
Transportation-related TBI prevention efforts can be
approached by looking at both passive and active meth-
ods, as well as using the Haddon Matrix discussed in an
earlier section.
Air Bags and Seat Belts
Air bags are a classic example of passive prevention that
exerts its influence at the time of incident. Jagger (1992)
has strongly advocated their use and has stated that
installing them as standard equipment in the front seats of
passenger cars would have a greater effect on TBI than
any other prevention method. She estimated that 25% of
patients admitted to a hospital secondary to TBI had sus-

tained an injury that air bags are designed to protect
against.
Air bags are automatic protection systems that are de-
signed to protect during a frontal collision. They are de-
signed to deploy when a car hits a similarly sized vehicle
at 20–30 miles an hour, or a brick wall at 15 miles an hour.
They provide a protective cushion between occupants
and the car’s interior, slowing the energy transfer that oc-
curs at impact. This occurs within
1
/20 of a second after
impact, and deflation begins within
4
/20 of a second, with
the entire cycle completed within 1 second. This allows
the driver to maintain control of the car and avoids trap-
ping of passengers (National Highway Traffic Safety Ad-
ministration 2002).
With the exception of some recently designed side-
impact bags, air bags have not been engineered to protect
the occupants from side impact, rear, or rollover events. One
of the major sources of crash mortality is ejection from the