Biology Reference
In-Depth Information
consequently increasing the permeability of the blood-brain barrier (BBB). The
resulting diffusion of serum proteins and the transmigration of blood cells into the
injured brain tissue are known to exacerbate cerebral damage. Experimental stud-
ies from our laboratory using mice subjected to focal TBI have shown that although
the passage of large molecules like horseradish peroxidase (44 kDa) injected intra-
venously occurs only in the acute phase (4-5 hours after TBI), smaller molecules
(286 Da or 10,000 Da) are still able to penetrate the brain at 4 days
[7]
. Understanding
the time course of BBB dysfunction is of particular relevance because such know-
ledge allows the identification of a therapeutic window for the administration of drugs
that cannot cross the intact BBB under physiological conditions.
As an interface between the periphery and the brain, the endothelium constitut-
ing the BBB is strongly affected by both cerebral and systemic changes, which can
significantly affect brain function. Endothelial cells are immunologically active and
express a variety of cytokines and cell adhesion molecules that regulate adherence
and infiltration of leukocytes into the injured site. The breakdown of the BBB plays a
profound role in the development of brain edema following TBI and the consequent
increase in intracranial pressure. Additional physiological events can affect the integ-
rity of the BBB by participating in the development of brain edema. One such insult
is posttraumatic hypoxia, which can significantly affect patients' outcomes after TBI
and is often associated with increased length of hospital stay, increased severity of
brain injury, and worse functional outcome.
Hypoxia
itself is defined as arterial oxy-
gen saturation (SaO
2
) of 90% and has been documented in up to 45% of all TBI
patients
[8]
. The imbalance in blood gases contributes to augmentation of cerebral
blood volume due to loss of autoregulation (ability of the vasculature to respond to
CO
2
-O
2
ratios by dilating or contracting), which exacerbates BBB permeability fur-
ther, allows the diffusion of serum proteins and blood cells in the parenchyma, and
causes cell swelling via excessive intracellular ion influx. Collectively, these pro-
cesses constitute the complex phenomenon of secondary brain damage
[9]
.
10.3 Molecular Cascades Mediating Cell Death after TBI
The pathological alterations resulting from brain injury trigger multiple biochemical
cascades that lead to the release of neurotoxic substances that ultimately exacerbate
neuronal cell death
[10]
. Occurring from the early hours to days following TBI, these
events establish a useful time frame for therapeutic intervention intended to block their
irreversible effects. The reduction of secondary brain injury through a modification of
these molecular pathways is the clinician's major task in the management of TBI.
Much research effort has been dedicated to establishing the roles of excitotoxicity,
the oxidative pathway, and cerebral inflammation after brain injury
[11]
. Recent human
studies have described, by volumetric brain MRI analysis, an ongoing progressive brain
atrophy up to 1 year following TBI, which correlated with altered brain metabolism
(lactate/pyruvate ratio) measured in the acute phase by microdialysis
[12-14]
. These
findings corroborate the significant tissue loss and delayed neuronal death observed
in TBI rodents that paradoxically coincides with neurological improvement
[15,16]
.
