Biology Reference
In-Depth Information
Apoptotic cell death predominantly occurs in neurons surrounding the lesion in focal
TBI models such as controlled cortical impact injury, fluid percussion injury, or closed
head injury, with peak levels occurring at 1-2 days postinjury and slowly decreasing
in subsequent days
[15,17-20]
. Several factors have been identified as potential trig-
gers of apoptosis, one of which seems to be the excessive production of glutamate,
the main excitotoxic neurotransmitter in the brain. Glutamate is abundantly released
within minutes after TBI as a consequence of increased neuronal production, release
by cell rupture, and the inefficiency of astrocytes to take up glutamate, which is nor-
mally metabolized intracellularly into harmless glutamine. Binding of glutamate to
N-methyl-D-aspartic acid (NMDA) receptors increases the influx of intracellular Ca
that causes mitochondrial overload and activation of caspase-dependent and indepen-
dent cell apoptosis. A great deal of experimental research, including a vast number of
randomized clinical trials, has focused on the neutralization of glutamate, specifically
by targeting its main receptor NMDA, with the aim of avoiding and improving tissue
and neurological damage. Unfortunately, most of these clinical trials were unable to
demonstrate therapeutic efficacy in humans, despite the abundance of successful pre-
clinical experiments in animal models
[3]
. Of note, based on findings from a mouse
model of TBI, Shohami's group recently speculated that the failure of such NMDA-
inhibiting compounds may be due to the fact that NMDA receptor hyperactivation is
only a transient phenomenon (within 1 hour), which is rapidly followed by a profound
and long-lasting loss of function
[21]
. Consistent with their hypothesis, the adminis-
tration of exogenous NMDA in TBI mice improved motor and cognitive recovery.
Apoptotic cell death occurs mostly via the extrinsic and intrinsic pathways. The
extrinsic pathway of apoptosis differs from the intrinsic pathway in that it is activated
by the interaction of a ligand with a membrane receptor. The death receptor Fas is the
most scrutinized mediator of extrinsic apoptosis, and implications from these studies is
relevant to TBI because Fas is expressed on neurons, rendering these cells highly sus-
ceptible to death. Delayed neuronal loss is particularly likely in the region surrounding
the lesion and more distally within the hippocampus. Following Fas-ligand binding,
the receptor undergoes trimerization, followed by the recruitment of FAS-Associated
protein with Death Domain (FADD) and activation by cleavage of caspases-8, which
in turn activates the executioner caspase-3 to cleave the enzyme DNase, allowing it to
enter the nucleus and break DNA into fragments (detected histologically by TUNEL
staining). Fas expression has been identified in dying TUNEL-positive neurons sur-
rounding the brain lesion and also on other cells, including astrocytes and microglia.
The pivotal role of Fas in mediating cell death and neurological deficit following TBI
is revealed by experiments on specific mouse strains with mutated, nonfunctional
expression of either Fas (
lpr
) or Fas ligand (
gld
). A neuroprotective effect was demon-
strated in ischemic and spinal cord injury models using
lpr
mutants, which displayed
reduced tissue damage and neuronal resilience to apoptosis
[22,23]
. However, in a
TBI model of controlled cortical impact injury, such benefits were noted only when
both Fas and the related pro-inflammatory cytokine tumor necrosis factor (TNF) were
simultaneously knocked out
[24]
.
In our laboratory, a sustained improvement of neurological deficit and reduction
of lesion volume were observed in
lpr
mice using a closed focal TBI model. These
