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Review
10.1517/13543784.15.11.1371 © 2006 Informa UK Ltd ISSN 1354-3784 1371
Central & Peripheral Nervous Systems
Recent advances in
neuroprotection for treating
traumatic brain injury
Ibolja Cernak
Johns Hopkins University Applied Physics Laboratory, Biomedicine Business Area, 11100 Johns Hopkins
Road, Laurel, MD 20723-6099, USA
The fact that traumatic brain injury is the leading cause of death and dis-
ability in the most active population (< 45 years of age) of industrialised
countries underscores the need for intensified efforts to define and imple-
ment effective neuroprotective strategies. However, despite progressively
growing knowledge on the mechanisms involved in the pathobiology of
traumatic brain injury and promising preclinical findings, most of the neuro-
protection trials have failed to deliver the expected level of beneficial effects.
Some of the possible reasons underlying the lack of success of these clinical
trials are addressed in this review, which describes some of the most pro-
mising and/or controversial ongoing clinical trials from their patho-
physiological basis. In addition, new neurobiological findings and their
consequence for novel neuroprotective approaches are discussed.
Keywords: nanotechnology, neuroprotection, traumatic brain injury
Expert Opin. Investig. Drugs (2006) 15(11):1371-1381
1. Introduction
Traumatic brain injury (TBI) has frequently been called ‘silent epidemic’ of the
modern world referring to the fact that TBI is the leading cause of death and
disability in the most active population (< 45 years of age) of industrialised coun-
tries
[1]. Moreover, recent data report that the incidence of TBI in the USA is close
to 1.4 million people/year and, among them, an estimated 80,000 – 90,000 experi-
ence the onset of long-term disability
[2]. These findings underscore the need for
intensified efforts to define and implement effective neuroprotective strategies.
Indeed, there is an increasing awareness of what the implications of TBI and its
long-term consequences for society in economic, social and human are. This
resulted in 58 currently ongoing clinical trials concerning preventive measures,
diagnosis, treatment and rehabilitation of TBI that are registered at the Clinical
Trials website
[201], a service of the US NIH and developed by the National Library
of Medicine. Interestingly, although numerous experimental studies showed pro-
mising neuroprotective effects in experimental models of TBI, almost all of the clin-
ical trials have failed to demonstrate significant success in treating brain-injured
patients
[3]. One of the reasons underlying the relatively small success of clinical tri-
als is the complexity of the pathobiology of TBI; that is, TBI inflicts not only direct
mechanical damage to tissue but initiates complex biochemical changes resulting in
delayed neural cell loss (
Figure 1) [4]. It has been established that secondary injury
mechanisms via intricate interactions play an essential role in chronic neurological
disability. The lack of success of previous therapeutic efforts targeting only one indi-
vidual factor may be explained by the multifactorial nature of TBI. Based on the
concept of delayed biochemical injury, many drugs have proven to be effective in
1. Introduction
2. Clinical trials and high hopes
3. Experimental promises
4. Conclusion
5. Expert opinion
Recent advances in neuroprotection for treating traumatic brain injury
1372 Expert Opin. Investig. Drugs (2006) 15(11)
experimental neurotrauma [4]; however, no pharmacotherapy
has yet been found to be effective in clinical head injury
[3].
The development of clinically relevant experimental mod-
els of TBI (which successfully replicate the most important
changes reported in clinical head injuries such as brain
oedema, elevated intracerebral pressure, reduced cortical per-
fusion, decreased cerebral blood flow, neuroendocrine and
metabolic changes, and coma as well as mechanisms under-
lying neuronal cell death and resulting neurological deficits
following TBI) represent a valuable tool for developing novel
therapeutic approaches for brain injuries
[5]. Indeed, a better
knowledge of the pathophysiological mechanisms of head
injuries prompted clinical researchers to design and imple-
ment various therapeutic approaches aiming to modify the
harmful mechanisms and improve the outcome. This review
describes some of the most promising and/or controversial
ongoing clinical trials and explains their pathophysiological
basis. In addition, new neurobiological findings and their
relevance for novel neuroprotective approaches are discussed.
2. Clinical trials and high hopes
2.1 Dexanabinol
Numerous clinical trials have been conducted in the past
without significant effects (see Section 1)
[4,6,7]. Among the
trials, which failed to deliver the expected level of neuro-
protection, were the evaluation of corticosteroids
[8], barbitu-
rates
[9], glutamate antagonists [10], free radical scavengers [11]
and Ca
2+
channel blockers [12,13]. One of the clinical trials
with high expectations tested the efficacy of dexanabinol, a
synthetic cannabinoid analogue
[14] with strong neuro-
protective potential demonstrated in experimental models of
TBI
[15,16]. Experimental studies using various models of TBI
demonstrated that dexanabinol targeted various
pathophysiological mechanisms involved in TBI-induced
neurological deficits; it reduced glutamate excitoxicity, free
radical production and inflammatory response
[17] among
others. After the Phase I trial showed that dexanabinol
≤ 200 mg was safe in healthy volunteers, Phase II results indi-
cated improved control of intracranial pressure
[18] and a
Phase III trial was instigated
[19]. It was a big disappointment
when the final results showed no improvements in the control
of intracranial pressure or quality of life in the group of dex-
anabinol-treated patients versus placebo-treated group and
the subgroup analysis reported no indication of differential
treatment effects
[19].
2.2 Magnesium salts
Although the mechanisms of neuroprotection by magnesium
are not fully understood, they include a reduction of
presynaptic release of glutamate and blocking the glutama-
tergic N-methyl-
D-aspartate receptors, as well as blockage of
Ca
2+
entry via voltage-gated Ca
2+
channels and potentiation
of adenosine action among others
[20]. Preclinical studies
using experimental models of TBI (which replicated con-
tusion, diffuse axonal injury, oedema and subarachnoid haem-
orrhage
[21,22]) demonstrated significant beneficial effects of
magnesium. Combined with findings of limited clinical stud-
ies involving patients with brain injury
[23,24], the results of
these studies suggest that magnesium salts (magnesium sulfate
and magnesium chloride) are promising neuroprotective
agents for clinical use
[4]. Surprisingly, the Phase III clinical
trial evaluating the effects of magnesium sulfate for brain
injury and organised by the University of Washington showed
a negative outcome, with an increase of ∼ 25% in mortality in
the treated group compared with placebo controls (Temkin
NR, personal communication). Together with the results of a
large-scale, randomised clinical trial using magnesium sulfate
Figure 1. Schematic presentation of the most essential mechanisms underlying neurological deficits caused by TBI.
ICP: Intracranial pressure; TBI: Traumatic brain injury.
Necrosis Apoptosis
Neuronal cell death
Increased ICP
TBI
Impaired cerebral
vasoregulation
Mechanical tissue
destruction
Secondary injury
mechanisms
Brain oedema
Decreased cerebral
perfusion
Cernak
Expert Opin. Investig. Drugs (2006) 15(11) 1373
in acute stroke [25] and some previous clinical studies [26,27],
these findings have tempered the initial enthusiasm for a
neuroprotective benefit of magnesium
[28]. Currently, there is
an ongoing clinical trial evaluating putative neuroprotective
effects of magnesium sulfate in premature infants (Thomas
Jefferson University).
Nevertheless, further data on magnesium’s neuroprotective
role in brain injury emerged with new studies. Chan et al.
[29]
reported that magnesium sulfate increased tissue oxygenation
and reduced hypoxia in patients undergoing temporary surgi-
cal artery occlusion. Moreover, van den Bergh et al. and the
MASH (Magnesium and Acetylsalicylic Acid in Subarachnoid
Hemorrhage) Study Group
[30] demonstrated that magnesium
sulfate therapy significantly reduced the frequency of delayed
cerebral ischaemia in patients with subarachnoidal haem-
orrhage. Recent experimental studies also report beneficial
effects of magnesium in TBI, thus further contributing to the
understanding of magnesium-related neuroprotection
[31,32].
Hopefully, further experimental studies and additional strictly
defined and controlled clinical trials will clarify whether mag-
nesium is neuroprotective in TBI and, if it is, under which
conditions and in which population.
It is noteworthy that both dexanabinol and magnesium are
multi-potential agents targeting several pivotal mechanisms
that result in long-term post-traumatic neurological deficits.
Why have these trials failed to deliver the highly expected
neuroprotection contrary to preclinical experimental studies?
There are multiple potential reasons for these failures
[33,34].
The first is the heterogeneity of the TBI patient population.
Indeed, these patients often have various degrees of tissue
damage, contusion, ischaemia, brain oedema, diffuse axonal
injury, and presence or absence of subarachnoidal haem-
orrhage. This amplifies the necessity of a stringent stratifica-
tion of patients into well-defined subgroups. Moreover,
clinical trials generally include patients with severe TBI, which
excludes the opportunity to analyse the effects of a treatment
on graded brain injury. Second, subjects included in clinical
trials are of both genders, whereas accumulating evidence
shows a distinct gender-dependent pathobiology of TBI
[35].
There are other aspects that could also significantly affect the
success of clinical trials; brain penetration, safety, tolerability
of the compound, and the interface between the pharma-
ceutical industry and academics are among the most
important factors
[36].
On the other hand, experimental studies standardise their
injury model to reproduce graded, usually moderate to severe,
neurological deficits in which positive therapeutic effects can be
statistically confirmed using the minimal number of animals.
Animals with severe injury that are not expected to benefit
from the treatment and those with mild injury that would
probably not show statistically observable benefit from the
drug are routinely excluded from research studies
[37]. More-
over, although mild TBI is the most frequently seen form of the
head injury in the human population, often underdiagnosed
and undertreated, animal ethics committees do not approve a
large experimental study of mild injury when a benefit has
already been demonstrated for moderate injury. All of these dif-
ferences in designing and analysing preclinical versus clinical
studies significantly contribute to obvious discrepancies in
study or trial outcomes.
2.3 Hypothermia
Currently, there are two ongoing clinical trials evaluating the
use of hypothermia in brain-injured patients that are reg-
istered
[101]. The first trial, NABIS:H (National Acute Brain
Injury Study: Hypothermia), was verified by the University of
Texas Health Science Center in September 2005. The
NABIS:H is a randomised clinical trial that will include ∼ 240
patients with severe brain injury aged 16 – 45 years and ran-
domised to standard treatment at normothermia or to stand-
ard treatment with moderate hypothermia (32.5 – 34°C for
48 h). Hypothermia will be induced to < 35.5°C by < 2.5 h
after severe TBI, reaching 33°C by 4 h after injury and main-
tained for 48 h. The primary outcome measures will be the
dichotomised Glasgow Outcome Scale (GOS; good outcome:
good recovery or moderate disability; poor outcome: severe
disability, vegetative or dead) and measured by blinded assess-
ment of patients at 6 months postinjury. The second study,
Therapeutic Hypothermia for Severe Traumatic Brain Injury
in Japan, is a Phase III multi-centre trial that was verified by
Yamaguchi University Hospital in August 2005. This
randomised clinical trial includes patients with severe TBI
(Glasgow Coma Scale [GCS] 4 – 8) of both genders and aged
15–69years. The participants are randomly assigned into
either the mild hypothermia (32 – 34°C) and anti-
hyperthermia (35 – 37°C) group. Hypothermia is induced
within 6 h after TBI and the body temperature is kept at these
levels for ≥ 72 h. The end point parameters (GOS and total
medical expenses) are evaluated at 6 months postinjury.
Experimental
[38,39] and pilot clinical [40,41] studies have
demonstrated the neuroprotective effects of moderate hypo-
thermia in brain ischaemia and TBI. The multifactorial
mechanisms through which hypothermia may protect the
brain include reducting metabolic rate, blocking of excito-
toxic mechanisms, Ca
2+
antagonism, preserving protein syn-
thesis, regulating cerebral blood flow, reducing brain
thermopooling, decreasing oedema development and modu-
lating inflammatory response
[42]. Due to highly encouraging
preclinical findings, the results of the multi-centre NABISH-1
(National Acute Brain Injury Study using Hypothermia 1)
trial evaluated the effects of brain cooling on TBI outcome
and have been awaited with great enthusiasm. However, the
final report of the NABISH-1 study, which was published in
the New England Journal of Medicine
[43], brought great dis-
appointment showing that moderate hypothermia failed to
improve the outcome of brain-injured patients. Briefly, a total
of 392 patients (16 – 65 years of age) with severe head injury
were enrolled, 193 of whom were assigned to standard treat-
ment and 199 to standard treatment plus hypothermia.
Moderate hypothermia (33°C) was initiated within 6 h of
Recent advances in neuroprotection for treating traumatic brain injury
1374 Expert Opin. Investig. Drugs (2006) 15(11)
injury and maintained for 48 h via surface cooling. The effi-
cacy of the treatment was measured by dichotomised GOS at
6 months postinjury. The analysis of results showed no signif-
icant difference in mortality. The lack of success was
explained by the differences in the percentages of patients
who were hypothermic on admission and in the protocols of
re-warming, imbalances in randomisation and wide variability
in management between the high- and low-enrolment centres
[43,44]. As moderate hypothermia has been shown to be one of
the most powerful neuroprotective methods in experimental
models of TBI and stroke, its lack to induce neuroprotection
in the clinical environment is a puzzling paradox. This may be
the reason for new clinical trials, which intend to use more
homogenous and strictly defined clinical protocols.
2.4 Decompressive craniectomy
High intracranial pressure (ICP) is one of the most frequent
causes of death and disability after severe TBI
[45,46].
Increased brain water content (i.e., brain oedema, increased
cerebral blood volumes and/or mass lesions) has been shown
as a key contributor to elevated ICP. Clinically relevant ICP
increase is generally defined as ICP above a threshold of
15 – 20 mmHg measured within subdural, intraventricular,
extradural or intraparenchymal compartments. Very often,
when high ICP is not associated with removable intracranial
mass (as in the case with diffuse brain swelling after TBI),
drug therapies are frequently unsuccessful to regulate
ICP
[47]. Currently, most trauma centres approach high ICP
using the recommendations of the Guidelines for the
Management of Severe Traumatic Brain Injury
[48]. These
guidelines include general maneuvers such as head elevation,
sedation, resuscitation and so on; CSF drainage, moderate
hypocapnia (i.e., partial pressure of CO
2
[pCO
2
] of
30–35mmHg) and mannitol administration as the first-line
therapeutic measures, and finally, the ‘second tier’ procedures,
which are indicated when the high ICP is refractory to previ-
ous measures. Decompressive craniectomy (DC), a method
to convert the confined-space skull into an open one by
removing a variable size of a bone
[49,50], besides high-dose
barbiturates and severe hyperhyperventilation (pCO
2
of
< 30 mmHg), belong to this group.
The DECRA (Early Decompressive Craniectomy in
Patients with Severe Traumatic Brain Injury) trial is a
multi-centre randomised trial verified by the National Trauma
Research Institute of Australia in September 2005. The goal
of this trial is to evaluate the effect of early DC on neuro-
logical function in patients with severe TBI. The DECRA
trial includes patients with severe TBI of both genders and
aged 15 – 60 years who admitted to the hospital within the
first 72 h from injury. Severe brain injury for the purpose of
inclusion criteria is defined as: GCS < 9 with computed tomo-
graphy (CT) scan showing evidence of brain oedema (grade
DII plus some evidence of DIII or DIV); GCS > 8 established
before intubation together with brain oedema graded as DIII
or DIV, and a CT scan showing basal cistern compression
with midline shift; or refractory ICP existing for > 15 min
continuously or cumulatively over 1 h, despite the best
conventional management (as defined in the study protocol).
Primary end point measures include GOS measured 6 months
after injury, whereas secondary outcomes are defined as mean
and maximum ICP measured hourly, in-hospital mortality
rate during 6 and 12 months, and number of days spent in the
intensive care unit of the hospital. The intended sample size is
499 patients from 40 centres. The RESCUE-ICP (Ran-
domised Evaluation of Surgery with Craniectomy for Uncon-
trollable Elevation of Intracranial Pressure) trial is another
currently ongoing clinical trial although it is not registered
[201]. The trial will include 400 patients of 10 – 65 years of age
with severe TBI and admitted in the specialised intensive care
units of 40 centres. A standard protocol is proposed to main-
tain ICP < 25 mmHg by applying treatment in 2 stages. After
these stages are unsuccessful in controlling ICP, the patients
will be randomised to continuation of medical management
versus DC
[42].
Interestingly, despite numerous small series and case reports
suggesting neuroprotective effects of DC in severe TBI
patients, a comprehensive review of the available literature
failed to show that the routine use of secondary DC sig-
nificantly improves the outcome in adults with severe TBI
and refractory high ICP
[42]. On the other hand, a small pro-
spective, randomised clinical trial of secondary DC, which
included 27 children (< 18 years of age) with severe TBI
(14 with medical management alone and 13 with DC and
medical treatment) demonstrated that DC effectively reduced
refractory ICP, decreased mortality and improved functional
outcome
[51]. This discrepancy may be caused by a funda-
mental difference between injury mechanisms in young com-
pared with adult brain. Indeed, it has been shown that
children more frequently develop diffuse cerebral swelling
after TBI compared with adults
[52], and that the
TBI-induced overactivation of ongoing physiological pro-
grammed neuronal death (apoptosis) is unique for the devel-
oping brain
[53]. Defining and taking into account the
age-dependent differences in the pathomechanisms of TBI are
necessary to develop new neuroprotective approaches, and
design and analyse clinical trials.
As DC is widely used in treating the civilian and military
adult population with severe head injury, regardless of the
obvious contradiction in the related literature, further
well-designed randomised multi-centre studies are needed
to clarify the potential values of DC. Hopefully, the
ongoing DECRA and RESCUE-ICP trials will take into
account some of the lessons learned in previous non-con-
trolled studies and recommendations made on the basis of
that knowledge
[42].
2.5 Therapy against brain oedema
Management of post-traumatic brain oedema remains largely
empirical and it has not changed in ∼ 50 years. Brain oedema,
a potentially devastating complication of TBI, is defined as an
Cernak
Expert Opin. Investig. Drugs (2006) 15(11) 1375
increased volume of the brain caused by pathological fluid
accumulation and has been established having significant role
in ICP increase, impairments in cerebral blood flow and
decreased cerebrospinal fluid
[54]. The exact mechanisms
underlying brain oedema formation following TBI are not
entirely clarified. Accumulating evidence suggest importance
of the blood–brain barrier (BBB) permeability
[55], the
NMDA receptors
[56], bradykinin [57], the matrix
metalloproteases (MMPs) of a family of proteases
[58],
aquaporin 4 (AQP4) of a family of membrane water-channel
proteins
[59,60] and neuropeptides (such as substance P [61,62])
in TBI-elicited brain oedema development.
Treatments used in clinical management of post-traumatic
brain oedema include mannitol
[63], hypertonic saline
(HTS)
[64] and steroids among others [65]. The two main
mechanisms of mannitol’s action are osmotic and haemo-
dynamic. As mannitol does not cross the intact BBB, it estab-
lishes a concentration gradient across the BBB forcing the
movement of water from the oedematous brain to the intra-
vascular space; this process is followed by fast renal excretion
of mannitol and water. The haemodynamic effects of manni-
tol are based on a reduction in blood viscosity, which conse-
quently leads to increased cerebral blood flow and decrease in
cerebral blood volume via passive vasoconstriction
[65].
Although mannitol 20% is routinely used to reduce brain
bulk and intracranial pressure, its use has never been subjected
to a randomised, placebo-controlled trial analysing its effects
on post-TBI outcome. It is also noteworthy that mannitol
causes diuresis leading to secondary effects (such as systemic
hypovolaemia and hypotension) and adverse changes in serum
and urinary Na
+
, K
+
and osmolarity, which can be deleterious
to the brain-injured patient.
Hypertonic saline solutions have been suggested as an alter-
native to mannitol for the treatment of brain oedema
[65]. It
has been demonstrated that through multiple and probably
interacting mechanisms (such as optimisation of systemic and
cerebral haemodynamics, modulation of cerebral vasospasm
and changes in neuroendocrine-immune parameters
[64])
HTSs reduce brain oedema and ICP. The adverse effects of
HTS are similar to other osmotic agents: osmotic demyelina-
tion syndrome, renal insufficiency and rebound intracranial
hypertension
[64]. Despite promising clinical data on hyper-
tonic saline
[66,67], controversy remains about the role of HTS
in the treatment of TBI-induced oedema. The results of a
larger multi-centre trial
[68] conducted in Australia showed no
improved neurological outcome in patients with severe brain
trauma and hypotension who received hypertonic saline for
pre-hospital resuscitation compared with conventional fluid
management. Further experimental and clinical studies are
necessary to fully define the precise mechanisms of actions,
optimise administration regimens and confirm the role of
HTS in brain oedema management.
As glucoroticoids (GCs) have been shown to ameliorate
vasogenic oedema accompanying tumour, inflammatory
conditions and other disorders linked to increased BBB
permeability
[69], they were incorporated as a standard part of
TBI-induced brain oedema management over the course of
40 years. Interestingly, numerous clinical trials conducted dur-
ing this period of time showed no proof of steroid efficacy in
improving post-traumatic outcome in patients with severe
head injury
[70]. The recent MRC CRASH (Corticosteroid
Randomisation After Significant Head injury) international
standard randomised controlled trial evaluated the effect of
corticosteroids on death and disability after head injury in
10,008 randomly allocated adults. Data at 6 months showed a
significantly increased risk of death in the GC than in the
placebo group and no evidence that the effect of GCs changed
with injury severity or time since injury
[8]. These results
further support the recommendation that GCs should not be
used for reducing ICP or improving outcome after severe TBI.
The broad array of recent experimental studies suggests
novel therapeutic possibilities in preventing and/or reducing
brain oedema after TBI: inhibition of the complement
cascade by N-acetylheparin in thrombin-induced brain dam-
age
[71], modulation of AQP-4 channels by magnesium [31,72]
or blocking bradykinin B
2
receptor [73] among others. Con-
tinuing research is needed to enhance the understanding of
the pathobiology of cerebral oedema and identify new
approaches against TBI-induced brain oedema.
2.6 Progesterone
Numerous experimental studies using various models of TBI
demonstrated that progesterone, a neurosteroid that is natu-
rally found in the brains of both men and women, has signifi-
cant neuroprotective properties
[74]. Progesterone confers its
neuroprotective action most possibly via multiple mecha-
nisms
[75]. This hormone has been shown to reduce neuronal
injury caused by glutamate, FeSO
4
and Aβ toxicity; decrease
post-traumatic brain oedema
[76] and anxiety [77]; reverse the
early postinjury dysfunction in mitochondrial respiration and
reduce hippocampal neuronal loss after TBI
[78]; has anti-
oxidant effects
[79]; and attenuates mechanisms of apoptotic
cell death
[80] and so on.
A recent study
[81] has shown that acute TBI per se does not
induce an endogenous release of progesterone and that stable
progesterone concentrations can be rapidly achieved by
continuous intravenous infusion in patients with acute to
severe TBI. Pharmacokinetic alterations observed in pro-
gesterone levels after TBI were not gender dependent
[81].
These results demonstrate a feasibility of progesterone treat-
ment in TBI patients. ProTECT (Progesterone for Traumatic
Brain Injury, Experimental Clinical Treatment) was a sin-
gle-centre, Phase II, double-blind, randomised, placebo-con-
trolled trial organised by Emory University to analyse the
effects of progesterone treatment on the outcome of moderate
and severe blunt TBI. The study started in May 2002, ended
in January 2006 and included patients of both genders, of
≥ 18 years of age with moderate to severe blunt head trauma
(GCS: 4 – 12) that occurred within 11 h. The preliminary
results seem to be promising.
Recent advances in neuroprotection for treating traumatic brain injury
1376 Expert Opin. Investig. Drugs (2006) 15(11)
3. Experimental promises
3.1 Neurotransplantation
As the brain has limited capacity for self repair, increasing
research efforts address the possibility of reducing func-
tional deficits caused by brain injury or disease by trans-
planting new cells or manipulating endogenous progenitor
cells that can replace those with irreversible damage
[82].
Tissue derived from the fetal CNS has been broadly evalu-
ated as a material for transplantation due to its pre-
disposition for long-term survival and ability to regain full
functionality
[83]; However, alternative sources of human
neurons for the purpose of transplantation have been devel-
oped, which include immortalised cell lines and cultured
stem cells
[84] because of ethical restrictions, lack of availa-
bility and immunological limitations. Postmitotic human
neurons (NT2N cells) derived from the human embryonal
tetracarcinoma (NT2 cell) line have demonstrated many of
the vital characteristics of normal developing and mature
human neurons
[85]. After the satisfying safety trial, Kondzi-
olka et al.
[86] implanted the NT2N cells stereotactically
into the brain of patients with motor deficits caused by
stroke. Despite the lack of a significant benefit in motor
function as determined by the primary efficacy measure
(i.e., European Stroke Scale at 6 months post-treatment), a
considerable improvement was observed in some patients
that manifested in improved quality of life. Stem cells are
undifferentiated cells that lack antigen markers typical of
mature cells and display significant proliferation potential,
whereas progenitor cells have a limited capacity for self
renewal and a more restricted lineage potential than that of
stem cell
[82]. Ideally, the transplanted cells should be able to
generate most or all subtypes of neurons and glial cells; cur-
rently, the embryonic stem cells are the best characterised
cells with such a feature
[87]. Although neurotransplantation
has great therapeutic potential, restoration of brain func-
tion after TBI requires more than just cellular replacement;
further knowledge on graft function, transplant-induced
molecular changes underlying behavioural recovery and
influence of environmental factors are necessary to achieve
a clinically relevant therapy for TBI. Currently, the Uni-
versity of Texas Health Science Center is conducting a
Phase I clinical trial aiming to determine if bone marrow
harvest-containing mesenchymal stem cells and haemato-
poietic stem cells, bone marrow precursor cell separation
and re-infusion are safe in children after severe TBI. The
study started in April 2006 and includes children of
5 – 14 years of age on the day of injury, with TBI occurring
< 24 h prior to injury and with a GCS of 5 – 8. Using chil-
dren as the primary population is justified by facts that chil-
dren are more likely to have isolated TBI that is more
diffuse and less likely to be secondary to extra-axial fluid
collections and that children have a greater neurological
plasticity compared with adults.
3.2 Cell-cycle inhibition
Upregulation of cell-cycle proteins has been shown in both
mitotic and postmitotic neural cells after brain injury in adult
animals. They induce proliferation in mitotic cells (such as
astroglia and microglia) but they stimulate caspase-dependent
apoptosis in postmitotic cells (such as neurons)
[88]. Recent
studies showed that early central administration of the cell-cycle
inhibitor flavopiridol after experimental TBI significantly
reduced lesion volume, scar formation and neuronal cell death
as well as promoting near complete behavioural recovery
[89].
Moreover, cell-cycle protein upregulation has been significantly
reduced, etoposide-induced neuronal cell death attenuated and
astrocyte proliferation decreased by using structurally different
cell-cycle inhibitors (flavopiridol, roscovitine and olomoucine)
in primary neuronal or astrocyte cultures. Flavopiridol also
reduced proliferation/activation of microglia in a con-
centration-dependent manner. It is noteworthy that central
administration of flavopiridol has been successful in improving
functional outcome in a dose-dependent manner after fluid
percussion induced brain injury in rats, whereas delayed sys-
temic administration of flavopiridol significantly decreased
brain lesion volume and attenuated oedema development after
TBI
[90]. Accumulating information [91] provides further sup-
port for the therapeutic potential of cell-cycle inhibitors for the
treatment of TBI, suggesting reduction of neuronal cell death,
inhibition of glial proliferation and attenuation of microglial
activation as the most likely protective mechanisms.
3.3 Small neuropeptides
Ample evidence shows neuroprotective effects of the tri-
peptide thyrotropin-releasing hormone (TRH) across multi-
ple experimental models of TBI
[92]. On the basis of the active
metabolic product of TRH, cyclo-His-Pro, a number of novel
cyclic dipeptides have been developed out of which four com-
pounds were found to reduce cell death after trophic with-
drawal or traumatic injury in primary neuronal cultures, and
two of these protected against glutamate or β-amyloid neuro-
toxicity
[93]. Interestingly, all of the compounds significantly
improved functional (motor and cognitive) outcome after
controlled cortical impact injury in mice and reduced brain
lesion volumes. The mechanisms of these small neuropeptides
are still not fully clarified. As a dipeptide, it would be
expected that these compounds confer their effects via recep-
tor system(s); however, the receptor-binding studies did not
show significant receptor binding of the prototype 35b to 50
classical receptors, channels or transporters
[93]. The mecha-
nisms suggested
[93] include attenuation of both apoptotic and
necrotic cell death pathways, reduction of intracellular Ca
2+
accumulation after injury, stabilisation of mitochondrial
membrane potential and a decrease in cytochrome c release.
Additional data have been presented showing that compound
35b, which is being developed for a clinical trial, decreased
injury-induced transcriptional changes for a number of genes
(and proteins) such as cell-cycle genes, aquaporins and
Cernak
Expert Opin. Investig. Drugs (2006) 15(11) 1377
cathepsins [94]. The fact that small neuropeptides upregulate
multiple endogenous neuroprotective factors and reduce
induction of multiple classic secondary injury mechanisms
suggests that they may have potential usefulness in clinical
head injury. Nevertheless, there is still a possibility that these
compounds confer their effects through at least one receptor
system; such an unidentified receptor–drug interaction could
cause multiple side effects and hence diminish the value of
this therapeutic approach for clinical use.
3.4 Anti-inflammatory strategies
Neuroinflammation has been shown to play a significant role in
the pathobiology of TBI. This complex process includes intricate
interactions between cytokines/chemokines, metalloproteases,
NO and the arachidonic acid cascade among others
[95,96].
Indeed, inflammatory mediators (such as IL-1, IL-6 and
TNF-α) have been demonstrated to play important roles in
delayed CNS damage. Moreover, administration of a COX-2
inhibitor after TBI improved functional outcome in rats suggest-
ing the importance of eicosanoids in post-traumatic neurological
deficits
[97,98]. Injury-induced neuronal cell loss was reduced
using a C5a receptor antagonist, whereas secondary injury mech-
anisms after TBI were attenuated by the lack of C3 or C5 com-
plement
[99]. Furthermore, neuropeptide (substance P) release
has been shown to significantly contribute to TBI-induced
neurogenic inflammation
[61,100], whereas substance P antagonist
significantly improved functional outcome in experimental ani-
mals with TBI
[62]. These findings suggest that factors of neuro-
genic inflammation are promising targets for the development of
novel and effective therapeutics for TBI.
4. Conclusion
It has now been accepted that TBI results in a multifactorial
secondary injury cascade that leads to neuronal cell death and
related long-term neurological deficits. Neuroprotective strat-
egies face challenge to identify and simultaneously target the
most important mechanisms involved in the secondary injury
cascade. Hence the most recent therapeutic candidates are
multifactorial in nature. These compounds show a greater
potential to become a ‘magic bullet’ drug compared with a
combination of drugs. The deficiencies of polypharmacy can
be explained by undesirable interactions of the individual
drugs and that multiple drugs have multiple side effects.
Current neuroscience applications concerning TBI are
focused on basic molecular and cellular mechanisms, some-
times without necessary consideration of their potential clinical
implications or analysing the time-line for possible translation
of the gained knowledge into clinical arena. Hence, therapeutic
approaches in early- and even late-stage clinical trials are often
repetitions of previous ones. There is an awareness of mistakes
in clinical design and data analysis, which could underlie nega-
tive outcome of TBI-related clinical trials; the new, higher
stringency design suggested by many scientists should increase
the reliability of information given by clinical trials.
5. Expert opinion
Despite immense research efforts and persisting enthusiasm,
the magic cocktail that would prevent delayed brain damage
and/or replace or regenerate the irreversibly injured cells after
TBI has yet to be found. Although knowledge on the patho-
biology of TBI (including mechanisms of neuronal cell
death, neurogenic inflammation and brain oedema and so
on) are progressively increasing, the quest for the Holy Grail
of neuroprotective therapies that would offer relief to an
enormous population of people suffering from the con-
sequences of TBI is still unsuccessful. There is an obvious
imbalance between extraordinary intellectual potential
invested into this research generating a vast amount of infor-
mation concerning brain injury and its therapy, and the lack
of success of clinical trials evaluating neuroprotective
strategies in TBI. Such a discrepancy suggests a need for ‘out
of the box’ thinking and fundamentally new approaches in
designing neuroprotective strategies.
Nanotechnology
[101] and molecular self assembly applied
to repair injured neuronal structures might offer such an
approach. Ellis-Behnke
[102] used a synthetic nanomaterial to
establish a permissive environment for axonal regrowth
in vivo. This impressive self-assembling protein created a
scaffold-like tissue-bridging structure and provided a frame-
work for partial axonal re-innervation with regenerative
potential both in young and adult animals. Moreover,
polymethylmethacrylate-covered silicon chips have also been
used as a nerve-regenerating scaffold with encouraging results
[103]. Carbon nanotubes made of rolled layers of graphite
have also been shown as potential devices that are able to
improve neural signal transfer by supporting dendrite elonga-
tion and cell adhesion
[104]. Design of functionalised nano-
particles that can be administered systemically and improve
drug delivery across the BBB is another clinically relevant
area of nanotechnology
[101]. Neuropeptides (such as
enkephalins) and the NMDA receptor antagonist
MRZ 2/576 have been absorbed onto the surface of
poly(butylcyanoacrylate) nanoparticles with polysorbate 80
coating; this coating adsorbs apolipoproteins B and -E from
the blood, which enables the uptake of nanoparticles by brain
capillary endothelial cells through receptor-mediated endo-
cytosis
[105]. There are numerous challenges related to the use
of nanotechnology in neuroscience. Structural complexity
and heterogeneity, the highly anatomically restrictive nature
of the CNS and the extremely intricate cellular interactions
cause a unique set of obstacles
[101]. Nevertheless, the applica-
tions of nanotechnology enable physical interaction with
neural cells at cellular and subcellular levels, with a potential
to establish functional interaction at a systemic level and
facilitate direct physiological effects. Taking together, nano-
technology offers enormous opportunities for further under-
standing of the pathobiology of TBI and (as such) might
represent one of the ‘out of the box’ research directions for
developing novel therapies.
Recent advances in neuroprotection for treating traumatic brain injury
1378 Expert Opin. Investig. Drugs (2006) 15(11)
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• Exciting possibilities of nanotechnology
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Website
201. http://www.ClinicalTrials.gov
Clinical trials website.
Affiliation
Ibolja Cernak MD PhD, Senior Professional Staff
Johns Hopkins University Applied Physics
Laboratory, Biomedicine Business Area,
11100 Johns Hopkins Road, Laurel,
MD 20723-6099, USA
Tel: +1 443 778 2637; Fax: +1 443 778 5889;
E-mail: ibolja.cernak@jhuapl.edu
