Summary. Traumatic brain injury (TBI) is a serious
neurodisorder commonly caused by car accidents, sports
related events or violence. Preventive measures are
highly recommended to reduce the risk and number of
TBI cases. The primary injury to the brain initiates a
secondary injury process that spreads via multiple
molecular mechanisms in the pathogenesis of TBI. The
events leading to both neurodegeneration and functional
recovery after TBI are generalized into four categories:
(i) primary injury that disrupts brain tissues; (ii)
secondary injury that causes pathophysiology in the
brain; (iii) inflammatory response that adds to
neurodegeneration; and (iv) repair-regeneration that may
contribute to neuronal repair and regeneration to some
extent following TBI. Destructive multiple mediators of
the secondary injury process ultimately dominate over a
few intrinsic protective measures, leading to activation
of cysteine proteases such as calpain and caspase-3 that
cleave key cellular substrates and cause cell death.
Experimental studies in rodent models of TBI suggest
that treatment with calpain inhibitors (e.g., AK295,
SJA6017) and neurotrophic factors (e.g., NGF, BDNF)
can prevent neuronal death and dysfunction in TBI.
Currently, there is still no precise therapeutic strategy for
the prevention of pathogenesis and neurodegeneration
following TBI in humans. The search continues to
explore new therapeutic targets and development of
promising drugs for the treatment of TBI.
Key words: TBI, Secondary injury, Calpain,
Neurodegeneration, Calpain inhibitors
It is noticed that TBI is often associated with an
elevation of ventricular intracranial pressure (ICP). A
high ICP indicates poor outcome after TBI (Marshall et
al., 1979). Steroids were known to improve neurological
function temporarily by diminishing brain swelling
associated with brain tumors. Because brain swelling
also occurs in TBI, steroids were thought to be effective
for the treatment of TBI. But, a series of clinical trials
made it clear that steroids did neither significantly
reduce ICP nor improve neurological function of the
patients with severe TBI. Indeed, the pathophysiology of
TBI is totally different from that of brain tumors. It is the
“secondary injury” that significantly contributes to the
prognosis of patients suffering from TBI. The
development of “fluid-percussion model“ of mechanical
brain injury (Sullivan et al., 1976) was able to
demonstrate diffuse axonal injury (DAI). This model
explained that high-speed motor vehicle accidents could
cause DAI without an impact to the head. Later, the
development of “controlled cortical contusion model“ of
experimental brain injury (Lighthall, 1988) was
successful to show the occurrence of DAI as well as
cortical contusion, a very common component of severe
TBI in humans. With the use of the rodent controlled
cortical contusion model (Dixon et al., 1991),
researchers were able to identify the pivotal role of
oxygen free radicals (Kontos, 1989; Hall, 1993) in the
progression of secondary injury. However, a clinical trial
with the scavenger of oxygen free radicals (Muizelaar et
al., 1993) alone did not result in significant functional
recovery after severe TBI. Recent studies have
documented the involvement of other factors such as
glutamate (Bullock and Fujisawa, 1992) and Ca2+-
dependent cysteine protease calpain (Kampfl et al.,
1996; Saatman et al., 1996a; Posmantur et al., 1997),
which are crucial for the pathogenesis during secondary
injury. Several drugs are being tested to prevent the
harmful effects of these crucial factors during secondary
injury (Saatman et al., 1996b; McIntosh et al., 1998;
Kupina et al., 2001). Current strategy for the treatment
of TBI should be designed to control secondary injury
before it causes an elevation of ICP and
Epidemiology of TBI
A study in the United States alone indicates that an
estimated 200 thousand victims of severe TBI require
Molecular mechanisms in the
pathogenesis of traumatic brain injury
S.K. Ray1, C.E. Dixon2and N.L. Banik1
1Department of Neurology, Clinical Science Building, Medical University of South Carolina, Charleston, SC, USA and
2Department of Neurosurgery, Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA, USA
Histol Histopathol (2002) 17: 1137-1152
Offprint requests to: Naren L. Banik, Ph.D., Department of Neurology,
Clinical Science Building, Medical University of South Carolina, 96
Jonathan Lucas Street, Suite 309, Charleston, SC 29425, USA. Fax:
843-792-8626. e-mail: email@example.com
Cellular and Molecular Biology
admission to the hospital every year and most of them
become permanently disabled, and another 1.74 million
victims experience mild TBI requiring doctor visit or
temporary disability of one day at least (Waxweiler et
al., 1995). Total costs for medical care and rehabilitation
of patients with TBI are estimated to exceed $40 billion
annually. Typically young people between the ages of 15
and 30 years are at the greatest risk of suffering from
TBI. Men are approximately twice as likely as women to
go through a TBI. Approximately 52 thousand deaths in
the United States are attributed to TBI every year.
Common causes of fatal TBI are automobiles, firearms,
bicycles, falls, sports and recreational activities, and
risky jobs. Automobile accidents are responsible for the
largest percentage of all types of TBI, and also the
predominate cause of fatal TBI in whites. Gunshot
wounds to the head account for the highest number of
deaths in young black males, followed by Hispanic and
Native American males. Some forms of TBI can be
prevented. The use of automobile seat belts may reduce
the risk of TBI-related morbidity and mortality. The
habit of wearing helmets may help decrease the number
and severity of TBI in motorcyclists and bicyclists.
Other preventive measures such as speed limit and drunk
driving laws may also help reduce the number of TBI
cases. It is warranted to focus on the prevention of a
large proportion of deaths from TBI by limiting access to
firearms, particularly handguns.
Types of TBI
An epidemiological study in the United States
classified the TBI severity (Frankowski, 1986) that
combined the symptoms and extent of brain injury as
previously determined by the Glasgow Coma Scale
(GCS) score (Teasdale and Jennett, 1974). As the most
widely used classification, the GCS enables
quantification of TBI severity based on patient’s
response to commands and stimuli. The GCS scores of 3
to 8, 9 to 12, and 13 to 15 represent severe, moderate,
and mild TBI, respectively. TBI severity can also be
classified into main five categories based on locations:
(i) extracranial injury, (ii) skull fracture, (iii) focal injury,
(iv) diffuse injury, and (v) penetrating injury. Diagnostic
procedures and practice patterns may influence TBI
classification and hospitalization. A TBI may be
considered severe in terms of its cost to the society, even
if the TBI patient is not hospitalized.
Pathophysiology of TBI
The events leading to pathophysiology as well as
functional recovery after TBI fall into four categories: (i)
primary injury that disrupts brain tissues at the moment
of mechanical impact; (ii) secondary injury that causes
pathophysiology in the brain with the production of high
levels of lactate, oxygen free radicals, interleukins,
glutamate, and intracellular free Ca2+in response to
primary injury; (iii) inflammatory response that adds to
neurodegeneration with the help of oxygen free radicals
and toxic neurochemicals; and (iv) repair-regeneration
that remains a poorly understood process, and it may
contribute to neuronal regeneration, axonal repair and
partial neurological recovery following TBI.
Generally, TBI is triggered by an external
mechanical impact to the head. An impact load causes
TBI through a combination of two injury mechanisms
such as contact and inertial forces (Graham et al., 1995).
Contact forces prevent the head from moving after the
impact. Inertial forces set the head in acceleration
(translational or rotational or both) with and without a
contact force. The two main patterns of head trauma are
focal and diffuse injuries. Contact forces cause focal
injuries such as skull fracture, epidural hematoma, coup
contusion, and subdural hematoma. Inertial forces with
only pure translational acceleration cause focal injuries
such as contracoup contusion, intracerebral hematoma,
and subdural hematoma. The inertial forces cause diffuse
injuries. The most common form of inertial forces is the
angular acceleration, a combination of translational
acceleration and rotational acceleration, which produces
every type of head trauma except skull fracture and
epidural hematoma. Rotational acceleration as a
significant component of the injury mechanism produces
concussion and DAI.
It is developed over a period of hours or days after
the initial impact to the head. Secondary injury is
associated with synthesis and release of neurochemicals
that alter cerebral blood flow, ion homeostasis, and
metabolism. Most of the post-traumatic neurochemical
mediators of secondary injury may act as
neurodestructive compounds. Identification of those
neurodestructive compounds and time of their
pathological actions can help design therapeutic
strategies to attenuate neuronal damage following TBI.
Oxygen free radicals and lipid peroxidation
Post-traumatic ischemia activates a cascade of
metabolic events leading to generation of oxygen free
radicals (Kontos and Povlishock, 1986; Ikeda and Long,
1990; Traystman et al., 1991). Post-traumatic non-
ischemic event such as the increase of intracellular free
Ca2+ concentration (through receptor-gated or voltage-
dependent ion channels) may also induce release of
oxygen free radicals from mitochondria (Kontos and
Povlishock, 1986; Tymianski and Tator, 1996).
Stimulation of enzymatic activities of cyclooxygenase,
monoamine oxidase, and nitric oxide synthase can
produce oxygen free radicals. The highly reactive
oxygen free radicals can cause damage by lipid
peroxidation in cell membrane, and oxidation of
Pathogenesis of TBI
intracellular proteins and nucleic acids. TBI may activate
phospholipases A2 and C to hydrolyze membrane
phospholipids releasing arachidonic acid. Formation of
pathogenic compounds such as free fatty acids (Dhillon
et al., 1994, 1995), leukotrienes (Kiwak et al., 1985;
Dhillon et al., 1996), and thromboxane B2 (DeWitt et
al., 1988) from the arachidonic acid cascade have been
associated with neurodegeneration and poor outcome
after experimental TBI.
The inhibitors of arachidonic acid cascade are
partially effective in experimental CNS injury. Ibuprofen
and indomethacin, inhibitors of cyclooxygenase, are
effective in improving cerebral metabolism in rats with
cortical freeze injury (Pappius and Wolfe, 1983), and
reducing neurological dysfunction in mice with weight-
drop brain injury (Hall, 1985). Extracellular ascorbate
was increased in the cerebral cortex after weight-drop
brain injury in rats (Hillered et al., 1990), indicating a
deficiency in intracellular anti-oxidant defense against
oxygen free radicals and lipid peroxidation. Anti-
oxidants and free radical scavengers have been
beneficial in experimental models of brain trauma (Wei
et al., 1981; Stein et al., 1991; Marklund et al., 2001).
For example, administration of 21-aminosteroid
U74006F, a potent oxygen free radical scavenger, could
reduce cerebral edema and mortality (McInctosh et al.,
1992), and improve motor function (Sanada et al., 1993)
of rats with brain injury. Subsequently, other
experimental brain injury studies also suggested 21-
aminosteroids to be effective in treating axonal injury
(Marion and White, 1996) and in reducing microvascular
permeability at the site of cortical injury (Mathew et al.,
1996). Although 21-aminosteroids generated promising
results in various animal models of TBI, they were not
significantly effective in the treatment of severe TBI in
Pre-treatment and acute post-treatment with D, α-
tocopheryl succinate plus polyethylene glycol attenuated
motor deficits following TBI (Clifton et al., 1989).
Analogues of α-tocopherol have also been reported to be
neuroprotective in mice following TBI (Grisar et al.,
1995). Lidocaine, a local anesthetic, has been found to
be a potent scavenger of hydroxyl radicals (Das and
Misra, 1992). Administration of lidocaine has been
reported to attenuate post injury neurological and motor
function, but not cognitive function (Muir et al., 1995).
Deferoxamine is an iron-chelating agent that can inhibit
the iron-dependent hydroxyl radical production, and has
been reported to improve spatial memory performance
following TBI (Long et al., 1996). Interestingly,
deferoxamine was found not to improve functional
outcome when combined with moderate hypothermia
treatment (Heegaard et al., 1997). Superoxide dismutase
(SOD) is a metalloenzyme, which catalyses the
dismutation of superoxide ion into oxygen and hydrogen
peroxide. Administration of polyethylene glycol-
conjugated SOD has been reported to reduce motor, but
not Morris water maze deficits following TBI (Hamm et
al., 1996). OPC-14117 is a superoxide scavenger that has
been reported to attenuate tissue damage (Mori et al.,
1998) and behavioral deficits (Kawamata et al., 1997)
following TBI. Early treatment with LY341122, an
inhibitor of lipid peroxidation and an antioxidant, has
been reported to provide significant histopathological
protection (Wada et al., 1999). Penicillamine is a
scavenging compound that has been reported to improve
motor performance in mice after TBI (Hall et al., 1999).
The pineal hormone melatonin, a scavenger of free
radicals, has been found to reduce contusion volume
following cortical impact in rats (Sarrafzadeh et al.,
2000). Endothelin-1, a 21-amino acid peptide, has been
closely linked to oxidative stress after traumatic brain
injury (Sato and Noble, 1998). The endothelin receptor
sub-type A antagonist, Ro 61-1790 has been shown to
attenuate Purkinje cell loss in the cerebellum following
Sequestration of calcium loads within the
mitochondrial matrix can open the mitochondrial
permeability transition pore leading to cellular oxidative
and metabolic stress. Acute treatment with cyclosporin
A (CsA), an inhibitor of Ca2+-induced mitochondrial
permeability transition pore, has been reported to reduce
tissue damage (Okonkwo et al., 1999; Scheff and
Sullivan, 1999; Sullivan et al., 2000b) and improve
motor function (Riess et al., 2001) following TBI in rats.
A single dose of CsA has also been reported to blunt
axonal damage following TBI (Buki et al., 1999).
Treatment with creatine, a common food supplement,
reduced cortical damage in both mice and rats (Sullivan
et al., 2000a). Protection seems to be related to creatine-
induced maintenance of mitochondrial bioenergetics.
Mitochondrial membrane potential was significantly
increased, intramitochondrial levels of reactive oxygen
species and calcium were significantly decreased, and
adenosine triphosphate levels were maintained.
Induction of mitochondrial permeability transition was
significantly inhibited in animals fed creatine. This food
supplement may provide clues to the mechanisms
responsible for neuronal loss after TBI and may find it
useful as a neuroprotective agent against acute and
delayed neurodegenerative processes.
Excitatory amino acids and excitotoxicity
Glutamate and aspartate are excitatory amino acids
(EAA) that are released in high concentrations in
extracellular space and cerebrospinal fluid (CSF) soon
after TBI (Faden et al., 1989; Palmer et al., 1993). Two
sequential mechanisms have been proposed for EAA
induced cell death or excitotoxicity that includes (i) an
influx of chloride and sodium ions (Cl-and Na+) leading
to acute neuronal and glial swelling, and (ii) an influx of
calcium ion (Ca2+) leading to delayed damage (Choi,
1987; Choi et al., 1987). Although glutamate binds to all
EAA receptors, selective ligands have been used to
characterize three major types of EAA receptors. The
first type of glutamate receptor binds N-methyl-D-
aspartate (NMDA) and is known as NMDA receptor,
Pathogenesis of TBI
which is a membrane complex associated with a
monovalent and divalent ion channel (ionophore).
Activation of NMDA receptor with subsequent opening
of the ionophore in a voltage-dependent manner allows
the influx of Na+ and Ca2+into the cell (Mayer et al.,
1984). Opening of the ionophore is facilitated by binding
of glycine to a specific site on the NMDA receptor
(Kleckner and Dingledine, 1988). The activity of
NMDA receptor can also be modulated by binding of
polyamines, which may augment or inhibit receptor
activation (Ransom and Stec, 1988). The zinc ion (Zn2+)
is also known to antagonize the binding of glycine to its
site (Yeh et al., 1990). The second type of glutamate
receptor binds excitatory ligand α-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid/kainic acid
(AMPA/KA) and is referred to as AMPA/KA receptor
(or non-NMDA receptor), which is associated with a
monovalent ion channel. The activation of AMPA/KA
receptor opens the associated ionophore in a non-
voltage-dependent manner, allowing the influx of Na+
and efflux of K+from the cell (Reynolds and Miller,
1988). A subtype of AMPA/KA receptor may also be
permeable to Ca2+(Iino et al., 1990). The third type of
glutamate receptor is metabotropic receptor that, unlike
ionotropic receptors, is associated with the activation of
an intracellular second messenger. Binding of glutamate
to this type of receptor activates phospholipase C (Wei et
al., 1982), which may induce the synthesis of inositol
triphosphate for releasing Ca2+from the intracellular
stores (Sugiyama et al., 1987). The regional distribution
of NMDA and non-NMDA receptors is directly related
to excitotoxicity in specific regions of the brain
following TBI (Miller et al., 1990). Hippocampus, which
plays a prominent role in learning and memory, has a
high density of glutamate receptors (Monaghan and
Cotman, 1986). Hippocampal dysfunctions, including a
suppression of long-term potentiation (Miyazaki et al.,
1992) and deficiency in learning and memory (Smith
et al., 1993a), have been reported following TBI in rats.
Pre-treatment with competitive NMDA receptor
antagonists has been effective to reduce EAA release
following TBI (Panter and Faden, 1992). However, a
multi-center human trial of Selfotel (a competitive
NMDA receptor antagonist) in the United States and
Europe was prematurely terminated because of serious
side effects associated with competitive NMDA receptor
antagonism. Pretreatment with noncompetitive NMDA
receptor antagonist such as phencyclidine (Hayes et al.,
1988) or MK-801 (McIntosh et al., 1988) attenuated
neurological dysfunctions following TBI in rats. Recent
studies also reported that pretreatment with MK-801
could reduce extracellular EAA rise in hippocampus
(Katoh et al., 1997), and enhance recovery of spatial
memory (Phillips et al., 1997) in rats after TBI.
Administration of ketamine, blocker of NMDA receptor-
associated ion channel, improved cognitive functions
after fluid-percussion brain injury (Smith et al., 1993b)
and reduced expression of several immediate early genes
(c-fos, fos B, jun B, and jun D) in cerebral cortex and
hippocampal dentate gyrus after focal mechanical brain
injury (Belluardo et al., 1995). Kynurenate (KYNA), an
antagonist of NMDA receptor-associated glycine
binding site, provided neuroprotection by preventing
loss of hippocampal neurons following TBI in rats
(Hicks et al., 1994). Administration of 6-cyano-7-
nitroquinoxaline-2,3-dione (CNQX), which has higher
affinity for AMPA/KA receptors than the glycine-
binding site of NMDA receptor, could reduce metabolic
dysfunction following brain injury (Kawamata et al.,
Dynorphin and neurodegeneration
Regional increase in endogenous opioid dynorphin,
a 17-amino acid peptide, has been found to correlate
with regional neurodegeneration after experimental brain
injury (McIntosh et al., 1987a). Dynorphin is thought to
be an endogenous ligand for the κ-opioid receptor
(Yoshimura et al., 1982), and has previously been
implicated as a mediator of secondary injury in spinal
cord trauma (Faden et al., 1985). Microinjections of
dynorphin and other κ-opioid agonists exacerbate
neurodysfunction in rats with brain injury (McIntosh et
al., 1994), supporting the concept that endogenous
opioid peptides contribute to the pathophysiology of
TBI. Impairment of the tail-flick reflex or motor
function due to dynorphin administration could be
prevented by treatment with NMDA antagonists (Caudle
and Isaac, 1988; Bakshi and Faden, 1990a). Also,
administration of antagonists of NMDA receptor-
associated glycine binding site could limit dynorphin-
induced neurological dysfunctions (Bakshi and Faden,
1990b). These studies suggest that dynorphin-induced
neurological dysfunctions involve the release of EAA
and excitotoxicity. However, the role of opioid receptors
in dynorphin-mediated neurodegeneration has been
controversial. Some studies have shown attenuation of
dynorphin-induced paralysis with opioid receptor
antagonists (Przewlocki et al., 1983; Spampinato and
Candeletti, 1985), whereas other studies have not found
prevention of paralysis with κ-opioid antagonists
(Stevens and Yaksh, 1986; Long et al., 1989). A later
report provides experimental evidence that both opioid
and non-opioid mechanisms may play a role in
dynorphin-induced neurological dysfunctions (Faden,
1990). Subsequent studies supported this hypothesis. For
example, dynorphin administration impaired motor
function through an opioid mechanism (Bakshi et al.,
1990), and caused neurodegeneratiion through a non-
opioid mechanism (Faden, 1992). Accumulation of
endogenous dynorphin (McIntosh et al., 1987b) as well
as release of EAA (Faden et al., 1989) as secondary
injury factors following TBI may be limited by treatment
with dynorphin antiserum or κ-opioid antagonists
(Faden, 1990) and NMDA antagonists (Faden and
Acetylcholine and cognitive deficits
Increase in concentration of acetylcholine and
Pathogenesis of TBI
decrease in binding of cholinergic receptors in the brain
have been found in experimental brain trauma (West et
al., 1981). Cholinergic hyper function occurred at acute
phase of trauma, but it changed to cholinergic hypo
function at the chronic phase after injury (Saija et al.,
1988; Dixon et al., 1996). Increased activity of
cholinergic systems or alteration of cholinergic receptors
in specific brain regions after TBI may contribute to
neurobehavioral dysfunction (Lyeth and Hayes, 1992).
Activation of cholinergic system after microinjection of
carbachol, a cholinergic agonist, manifests a reversible
loss of consciousness identical to that occurs after fluid-
percussion brain injury (Leonard et al., 1994). Both
depletion of acetylcholine concentrations and
obstruction of muscarinic cholinergic receptors in the
brain substantially attenuated the transient loss of
consciousness and enduring neurodysfunctions
associated with fluid-percussion brain injury (Hayes et
al., 1984). Administration of scopolamine, an anti-
cholinergic compound, decreased neurologic deficits in
experimental brain injury (Lyeth et al., 1992; Phillips et
al., 1997), indicating involvement of cholinergic system
in cognitive dysfunction. To this end, post-injury
administration of BIBN 99, a selective antagonist of the
muscarinic M2 cholinergic receptor (Pike and Hamm,
1995), or chronic administration of LU 25-109-T, a
partial muscarinic M1 cholinergic receptor agonist (Pike
and Hamm, 1997), has been shown to improve cognitive
function following experimental brain trauma in rats.
Probably, a change from cholinergic hyper function to
hypo function during the pathophysiological process of
injury requires a change in therapeutic strategy from
cholinergic antagonists to agonists. Taken together, the
experimental results suggest that anti-cholinergic agents
may restore reflexive and motor function in acute post-
traumatic period, while cholinomimetic compounds may
reduce long-term cognitive dysfunction. Since these
therapeutic agents work in the opposite directions with
respect to their pharmacological effects, the timing of
therapy with these agents appears to be critical.
Altered ion concentrations and pathogenesis
Potassium ion (K+) release into the extracellular
space has been detected after TBI (Takahashi et al.,
1981). Such K+release seems to be related to
widespread depolarization (Takahashi et al., 1981;
Katayama et al., 1990), and spreading of depression in
cerebral cortex (Sugaya et al., 1975). Acute increases in
K+interfere with membrane transport systems,
metabolisms, and synaptic functions (Kimelberg et al.,
1979). High levels of extracellular K+may also disrupt
energy homeostasis after brain injury (Hansen, 1985).
Further K+stimulates oxygen uptake in glial cells (Hertz
et al., 1973) and deprives traumatized neurons of their
oxygen supply. As a result anoxic neuronal damage may
occur in brain regions after the injury (Siesjo, 1981).
Magnesium ion (Mg2+) is critical for such cellular
processes as glycolysis, respiration, oxidative
phosphorylation, the biosyntheses of DNA, RNA and
protein, and maintenance of Na+and K+gradients
(Aikawa, 1980). A significant decrease in intracellular
free Mg2+concentrations soon after TBI has been
reported (Vink et al., 1988). Additional investigation
indicated prolongation of the decline in Mg2+
concentrations in the brain after TBI in rats (Vink et al.,
1996). Decreased Mg2+concentrations may impair
glucose utilization, energy metabolism, oxidative
phosphorylation, and biosynthetic pathways,
contributing to regional neurodegeneration after brain
trauma. As Mg2+regulates transport and accumulation
of calcium ion (Ca2+) in the cells, an alteration in Mg2+
concentrations in the brain may cause Ca2+mediated
neurotoxicity after TBI. Exogenous magnesium has been
demonstrated to be neuroprotective to both functional
and morphological deficits following TBI.
Administration of magnesium 1-hour post-injury
produced significant improvement in neurological
function at 18 and 48 hours after injury (Feldman et al.,
1996). Animals treated with MgCl2for 30 min after
injury has been reported to protect against neurological
deficits (McIntosh et al., 1989). One-hour post-treatment
with MgCl2has been reported to reduce TBI-induced
damage to the cortex, but did not alter post-traumatic
cell loss in the CA3 region of the ipsilateral cortex
(Bareyre et al., 2000). Administration of MgSO4has
been reported to attenuate recovery of function when
administered up to 12 hours post injury (Heath and Vink,
Ca2+plays an important role in initiation of the
pathophysiological pathways leading to neuro-
degeneration after CNS trauma (Tymianski and Tator,
1996; McIntosh et al., 1997). The elevated intracellular
Ca2+levels have been reported in brain regions after
TBI (Shapira et al., 1989; Fineman et al., 1993). The
decrease in extracellular Ca2+levels following cortical
compression contusion brain injury in rats was
associated with profound functional disabilities (Nilsson
et al., 1993), and the pre-treatment with glutamate
receptor antagonists did not decrease in extracellular
Ca2+levels (Nilsson et al., 1996). A recent study
suggested that excessive intracellular Ca2+resulting
from TBI in rats was adsorbed on mitochondrial
membrane to inhibit electron transport chain and energy
metabolism (Xiong et al., 1997).
It has been proposed that activated ion channels
following TBI may contribute to prolonged changes in
Ca2+homeostasis (Gennarelli et al., 1998). Ca2+channel
blockers to reduce excessive accumulation of
intracellular Ca2+have been examined as possible
neuroprotective agents for experimental TBI. Post injury
administration of the voltage-sensitive Ca2+channel
blocker Ziconotide (also SNX-111 and CI-1009) has
been reported to attenuate motor and cognitive deficits
(Berman et al., 2000). Similarly, post-injury treatment
with LOE 908, a broad-spectrum inhibitor of voltage-
operated cation channels and store-operated cation
channels has been demonstrated to reduce neuromotor
Pathogenesis of TBI
and visuospatial memory deficits (Cheney et al., 2000).
Pharmacologically blocking Ca2+entry has been another
important strategy to reduce post-injury excitotoxicity.
Treatment with (S)-emopamil, a Ca2+channel blocker,
has been reported to attenuate post-injury motor deficits
(Okiyama et al., 1992). Inhibiting polyamine-dependent
Ca2+influx is another therapeutic target for attenuating
post-injury excitotoxicity. Ifenprodil, a polyamine-site
NMDA receptor antagonist, has been reported to reduce
cortical injury volume after TBI (Dempsey et al., 2000).
Administration of voltage-sensitive Ca2+channel
blockers provided little success in treating brain injury in
humans (Baethman and Jansen, 1986; Robinson and
Teasdale, 1990). Dihydropyridine Ca2+channel blockers
including nimodipine have recently been evaluated in
clinical trials in TBI. Early trials reported beneficial
effects of nimodipine in severe head injury in humans
(Kostron et al., 1984). More recent trials with both
nicardipine and nimodipine did not show clinical benefit
in patients with TBI (Compton et al., 1990; Teasdale et
al., 1992). Thus, therapeutic efficacy of Ca2+channel
blockers in TBI remains controversial. Experimental
brain injury in rodent models indicated the increase in
mRNA expression of immediate early genes (IEG) such
as c-fos (Phillips and Belardo, 1992), and c-jun and jun
B (Raghupathi and McIntosh, 1996). The pattern of
induction of IEG in fluid-percussion brain injury is
similar to that found in seizure (Gass et al., 1993) and
ischemia (Wessel et al., 1991; An et al., 1993). However,
it is not yet confirmed that induction of IEG contributes
to the pathophysiological process in TBI. Members of
the fos and jun families function as transcription factors
and may mediate adaptive responses in the stimulated
nervous system (Morgan and Curran, 1991). The
heterodimer of c-Fos and c-Jun proteins regulates the
expression of genes for endogenous opioid peptide
(Morgan and Curran, 1991), amyloid ß-protein precursor
(Quitschke and Goldgaber, 1992), and nerve growth
factor (D’Mello and Heinrich, 1991), all of which are
overexpressed in TBI (McIntosh et al., 1987a; Pierce et
al., 1996). Further, the expression of c-fos (Smeyne et
al., 1993) and c-jun (Dragunow et al., 1993) has been
associated with apoptosis or programmed cell death
(PCD), which is also known to occur in TBI (Colicos
and Dash, 1996; Yakovlev et al., 1997; Conti et al.,
1998; Newcomb et al., 1999).
Activation of cysteine proteases and apoptosis
Cysteine proteases such as caspase and calpain can
play important role for mediation of cell death following
TBI. Although activation of caspase-3 via the extrinsic
and intrinsic apoptotic pathways after moderate TBI has
been documented (Beer et al., 2000; Keane et al., 2001),
experimental studies strongly suggest that calpain is
more important than caspase-3 for mediation of cell
death after TBI (Kampfl et al., 1997; Pike et al., 1998,
2001; Hayes et al., 1999). Calpain activation may occur
upstream of caspase-3 for mediation of apoptosis as
suggested by recent in vitro (Waterhouse et al., 1998)
and in vivo (Ray et al., 2001) studies. The increase in
intracellular Ca2+after TBI certainly activates Ca2+-
dependent proteases including calpain, which mediates
cytoskeletal protein degradation and neurodegeneration
in humans (McCracken et al., 1999; Huang and Wang,
2001) and rodents (Kampfl et al., 1996, 1997; Saatman
et al., 1996a; Hayes et al., 1999; Pike et al., 2001).
Overexpression and activation of calpain degrade
neurofilament protein (Banik et al., 1997) and α-fodrin
(Ray et al., 1999a) following spinal cord injury in rats.
Thus, a pathophysiological role for calpain has also been
implicated in spinal cord trauma (Banik et al., 1999).
Recent studies used calpain inhibitors such as calpeptin
and MDL-28170 (Fig. 1) to demonstrate the involvement
of calpain in apoptotic death of rat glial (Ray et al.,
1999b) and neuronal (Ray et al., 2000) cells,
respectively. Other calpain inhibitors such as calpain
inhibitor II, AK295, and SJA6017 (Fig. 1) in rodent
models attenuated the loss of cytoskeletal proteins after
cortical impact brain injury (Posmantur et al., 1997) and
improved functional outcome after fluid-percussion
Pathogenesis of TBI
Fig. 1. Various calpain inhibitors known to inhibit CNS cell death. These
are cell permeable and active site-targeted calpain inhibitors. Calpeptin
and MDL-28170 are structurally similar synthetic N-protected dipeptidyl
aldehyde. Calpeptin and MDL-27180 inhibited apoptosis of C6 glial (Ray
et al., 1999b) and PC12 neuronal (Ray et al., 2000) cells in culture.
Calpain inhibitor II is a synthetic tripeptidyl aldehyde capable of
preventing proteolysis and neuronal apoptosis (Villa et al., 1998). AK295
is a synthetic dipeptidyl α-keto amide that inhibits calpain-mediated
neurodegeneration in vivo (Bartus et al., 1994). SJA6017 is a new N-
protected dipeptidyl aldehyde capable of inhibiting calpain (Fukiage et
al., 1997). Neuroprotection in rodent models of TBI has been reported
using calpain inhibitor II (Posmantur et al., 1997), AK295 (Saatman et
al., 1996b), and SJA6017 (Kupina et al., 2001).
brain injury (Saatman et al., 1996b) and diffuse brain
injury (Kupina et al., 2001). Calpain inhibitors are
capable of providing neuroprotection both in vitro and in
vivo models suggesting that calpain inhibition can be an
important therapeutic strategy in TBI.
TBI can induce neuronal cells to synthesize and
secret inflammatory cytokines such as the peptides of
interleukin (IL) family and tumor necrosis factor-α
(TNF-α). The patients with severe head injuries had
increased levels of IL-1, IL-6, and TNF-α in circulation
and cerebro spinal fluid (Young et al., 1988; Goodman et
al., 1990; McClain et al., 1991; Ott et al., 1994).
Experimental TBI in animal models showed
upregulation of IL-1, IL-6, and TNF-α (Woodroofe et
al., 1991; Taupin et al., 1993; Shohami et al., 1994). The
light and electron microscopic studies indicated a rapid
microglial reaction in the dentate gyrus following
induction of lesion in the rat cortex (Gehrmann et al.,
1991). Activated microglia may be responsible for
production of IL-1 and IL-6 in rat brain following
mechanical injury (Woodroofe et al., 1991). The
accumulation of activated microglia has temporally been
associated with vulnerability of Purkinje cells to TBI
(Fukuda et al., 1996). Experimental brain injury in rats
induced mRNA expression of both IL-1ß (Fan et al.,
1995) and TNF-α (Fan et al., 1996) within the brain
regions. The induction of mRNA expression of these
cytokines occurred concomitantly with an increase in
mRNA expression of glial fibrillary acidic protein
(GFAP), an indication of astrogliosis in the
pathophysiological process of TBI. Astrogliosis has later
been shown to be associated with the upregulation of
inflammatory cytokines such as IL-1α, IL-1ß, and TNF-
α in traumatic murine brain (Rostworowski et al., 1997).
Percussive injury to human cerebral microvascular
endothelium in culture induced production of IL-1ß and
TNF-α (Gourin and Shackford, 1997), suggesting
participation of endothelial cells in the inflammatory
response after TBI. Acute increase in IL-1ß and TNF-α
may trigger synthesis and release of highly neurotoxic
agents such as arachidonic acid and its metabolites
(Rothwell and Relton, 1993).
Breakdown of blood-brain-barrier (BBB) and
infiltration of peripheral immune cells (neutrophils and
macrophages) into the brain parenchyma have been
reported previously in fluid-percussion brain injury in
rats (Cortez et al., 1989) and recently in human brain
contusion (Holmin et al., 1998). Infiltration of NK cells,
helper T cells, and cytotoxic T cells also occurred as
demonstrated by immunocytochemical studies following
weight-drop brain injury in rats (Holmin et al., 1995).
Early accumulation of neutrophils or polymorphonuclear
leukocytes following TBI in rats has been directly linked
to the development of cerebral edema (Schoettle et al.,
1990; Biagas et al., 1992). Accumulation of leukocytes
after TBI contributes to the secondary injury including
reduced cerebral blood flow, increased edema and
elevated ICP (Zhuang et al., 1993). Activated
macrophages that cross BBB and activated microglia
within the brain have been indicted as the main culprits
in causing progressive neurodegeneration after brain
trauma, because they release cytotoxic agents including
oxygen free radicals and inflammatory cytokines
(Thomas, 1992; Kreutzberg, 1996; Popovich et al.,
Platelet activating factor produced by various cells
such as platelets, neutrophils, monocytes, macrophages,
neurons, and endothelial cells may enhance BBB
permeability and constriction of cerebrovascular system
(Armstead et al., 1988; Kochanek et al., 1988). The toxic
role of platelet activating factor has been described in
neuropathological processes (Kornecki and Ehrlich,
1988; Frerichs and Feuerstein, 1990). Because the
platelet activating factor increases intracellular free Ca2+
levels in cultured neurons, it may contribute to Ca2+
mediated neuronal death following TBI.
Tissue damage in TBI may cause migration and
adhesion of leukocytes to the endothelium with
upregulation of intracellular adhesion molecule-1
(ICAM-1), which is a member of the immunoglobulin
supergene family. Following TBI in rats, upregulation of
ICAM-1 has been reported in cerebral microvessels
(Isaksson et al., 1997) and suggested to cause
sensorimotor deficit (Rancan et al., 2001). Expression of
ICAM-1 in astroglia following brain injury in rats
required participation of IL-1ß (Shibayama et al., 1996).
However, a recent study found that treatment of TBI rats
with the monoclonal antibodies to ICAM-1 did not
significantly change the functional or histopathological
outcome (Isaksson et al., 2001). Complement system has
also been suggested to play a prominent role in causing
neurodegeneration after TBI (Mollnes and Fosse, 1994).
An increase in complement mRNA has been reported
following experimental brain lesioning (Johnson et al.,
Anti-inflammatory strategies have recently been
initiated in the treatment of TBI. The accumulation of
neutrophils has been successfully inhibited by treatment
with soluble complement receptor-1 after TBI in rats
(Kaczorowski et al., 1995). Administration of the IL-1
receptor antagonist provided neuroprotection reducing
the extent of neuronal damage after fluid-percussion
brain injury in rats (Toulmond and Rothwell, 1995). The
inhibition of biosynthesis or activity of TNF-α in the
brain could significantly reduce cerebral edema and
improve motor function in rats with weight-drop brain
injury (Shohami et al., 1996). Although monoclonal
antibodies against ICAM-1 have been shown to be
effective in reducing edema and neurodysfunctions in
ischemia (Clark et al., 1991; Zhang et al., 1994) and
spinal cord injury (Hamada et al., 1996), their efficacy in
TBI has not yet been tested. Treatment with IL-10 has
been reported to enhance neurological recovery
following TBI (Knoblach and Faden, 1998). Blockade of
P-selectin has been reported to reduce probe trial
Pathogenesis of TBI
performance on a Morris water maze task following TBI
(Grady et al., 1999). Systemic administration of a high,
but not a low dose of IL-1 receptor antagonist has been
reported to attenuate neurological recovery after TBI
(Sanderson et al., 1999). The same study observed that
motor function was impaired by the high dose of IL-1
receptor antagonist (Sanderson et al., 1999).
Administration of anti-CD11b, a monoclonal antibody
directed against the leukocyte adhesion molecule
CD11b, reduced neurophil influx after TBI, but did not
improve function (Weaver et al., 2000). Nitric oxide
(NO) biosynthesized by the inducible NO synthase
(iNOS) is an inflammatory product implicated both in
secondary damage and in recovery from brain injury.
Rats treated with iNOS inhibitors aminoguanidine and
L-N-iminoethyl-lysine exacerbated functional outcome
and histological damage (Sinz, et al., 1999), thereby
suggesting a beneficial role for iNOS in TBI.
It should be noted that most of the TBI studies
suggested involvement of cytokines in mediation of
neurotoxic effects, while some CNS injury studies
reported the participation of cytokines in neuronal
survival (Brenneman et al., 1992) and neuroprotection
(Hori et al., 1996). Administration of recombinant IL-6
has been claimed to be neuroprotective after permanent
focal cerebral ischemia in rats (Loddick et al., 1998).
Mice lacking TNF receptors were highly susceptible to
cerebrotoxic and ischemic brain injury, suggesting a
neuroprotective role for TNF (Bruce et al., 1996). Pre-
treatmet with TNF-α has subsequently been shown to be
neuroprotective in focal cerebral ischemia in mice
(Nawashiro et al., 1997). Other neuroprotective effects
of cytokines may be observed in stimulation of astrocyte
proliferation, inhibition of Ca2+influx, induction of
macrophage host-defense mechanism, and stimulation of
neurotrophic factor biosynthesis (Rothwell and Relton,
In response to traumatic CNS injury, probably an
attempt is made to activate repair mechanisms and
stimulate neuroregeneration (Varon et al., 1991). The
recovery from traumatic injury may be facilitated with
the presence of peptide neurotrophic factors such as
nerve growth factor (NGF), brain-derived neurotrophic
factor (BDNF), glia-derived neurotrophic factor
(GDNF), and neurotrophin-3 (NT-3). Readily available
neurotrophic factors following TBI may support
neuronal survival, stimulate neurite sprouting (neuronal
plasticity), induce neuronal repair, and re-establish
functional connections in the brain. Acute increase in
NGF concentrations has been reported after penetrating
brain injury (Nieto-Sampedro et al., 1982), cortical
ablation (Whittemore et al., 1985), or deafferentation
(Needels et al., 1986). Induction in mRNA expression of
NGF receptor (NGFR) has been associated with
neuronal survival and plasticity following fimbria-
formix and angular bundle transections (Gibbs et al.,
1991). A recent study has suggested that astrocytes are
the major source of NGF upregulation following TBI in
rats (Goss et al., 1998). Although a marked increase in
expression of NGF at the mRNA and protein levels
occurred in acute traumatic phase after cortical
contusion injury (DeKosky et al., 1994), a significant
loss of NGFR immunoreactive neurons occurred in
chronic traumatic phase after fluid-percussion brain
injury (Leonard et al., 1994). Hippocampal mRNA
expression of BDNF was significantly increased in the
dentate gyrus at 3 hours, whereas mRNA expression of
NT-3 was decreased in the dentate gyrus at 6 and 24
hours after experimental brain injury in rats (Hicks et al.,
1997). Following severe controlled cortical impact
injury, NGF and BDNF mRNAs were early, transiently
and significantly upregulated while ciliary neurotrophic
factor (CNTF) was slow and less amplified in both the
area of the lesion and a remote region (Oyesiku et al.,
1999). Their respective receptors were also analyzed
showing that trkA and trkB mRNAs were significantly
elevated while CNTF receptor α (CNTFRα) was
significantly downregulated. An increase in GDNF has
been demonstrated following destruction of dorsal
hippocampus (Bakhit et al., 1991).
Therapeutic strategies with the administration of
neurotrophic factors following TBI have been found to
be neuroprotective. Treatment with NGF prevented
Pathogenesis of TBI
Fig. 2. The effects of intraventricular NGF treatment on spatial memory
retention after TB in rats. A bar graph with swim latencies (± SEM) of
animals is shown to find a submerged hidden platform. Animals were
trained before TBI and retested one week after injury. A mini-osmotic
pump (Alza Scientific products) was used to deliver vehicle (artificial
cerebrospinal fluid) or vehicle with NGF (2.5S form, 25 µg/ml) to the
animals. Vehicle-treated TBI animals (n=10) had longer swim latencies
to find the hidden platform compared to sham groups (n=8) indicating
that TBI produced spatial memory retention deficits. NFG-treated TBI
animals (n=10) had significantly (*, p<0.05) shorter swim latencies than
vehicle-treaded TBI animals (n=10) indicating an attenuation of spatial
memory retention deficits by NGF treatment. (Modified from Dixon et al.,
cholinergic neuronal death in hippocampus (Kromer,
1987). Central infusion of NGF could reduce the extent
of apoptotic cell death in septal cholinergic neurons and
improve cognitive function (Sinson et al., 1997) and to
restore cholinergic neurotransmission deficits (Dixon et
al., 1997) following experimental brain injury. Spatial
memory deficit following TBI may be related to
decreased capacity of cholinergic neurons to produce
acetylcholine. Indeed, our experimental study suggests
that spatial memory deficit following TBI in rats is
mediated by chronic deficits in cholinergic systems that
can be improved by neurotrophic factors such as NGF
(Fig. 2). Central infusion of BDNF attenuated neuronal
cell death following selective brain injury in rodent
(Hofer and Barde, 1988). Thus studies in animal models
suggest that therapeutic potential of neurotrophic factors
should be evaluated in clinical trials for neuroprotection
Investigations in animal models revealed distinct
cellular and molecular events, which contribute to the
pathogenesis, neurodegeneration, motor dysfunction,
and cognitive deficits following TBI. It appears that
precautions and preventive measures may dramatically
reduce the risk of mechanical primary injury to the brain.
A simplified schematic presentation shows several
known molecular mechanisms in the pathogenesis of
TBI (Fig. 3). Secondary injury cascades are certainly
responsible for progression of pathophysiological
processes after TBI. The inter-relationships among
diverse destructive mediators of the secondary injury
make it easy to enhance the neuronal damage and death,
while a limited number of repair and regeneration
activities ultimately cannot win to prevent the
pathophysiological processes (Fig. 3). Thus, therapeutic
intervention is a necessity to avoid neurodysfunction and
ameliorate pain following TBI. It is important to make
appropriate therapeutic interventions as early as
possible. A therapeutic agent targeted to a single factor
or pathway of secondary injury may not provide enough
neuroprotection, especially if the therapy begins in the
chronic phase of brain trauma. More than one
therapeutic agent may be considered in order to inhibit
progressive neurodegeneration resulting from the actions
of various mediators of secondary injury at a later stage.
Experimental studies suggest that cysteine protease
inhibitors in combination with neurotrophic factors may
inhibit neurodegeneration and reduce cognitive deficits
in TBI. However, the search continues to find out the
appropriate therapeutic agents for providing
neuroprotection in TBI (Faden, 2001). Time is an
important issue in the treatment of TBI. Therefore,
future investigations should be focused on identification
of timing of specific cellular and molecular events that
lead to delayed neuronal death and dysfunction. It is
anticipated that further development of novel therapeutic
agents based on the latest research knowledge should
help the treatment of TBI in the 21st century.
Acknowledgements. This work was supported in part by grants from the
National Institutes of Health (NS-31622, NS-38146, and NS40125),
National Multiple Sclerosis Society (RG-2130), and American Health
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