Biology Reference
In-Depth Information
following SAH in both humans and animal studies (
29, 30
).
Mitochondrial production of superoxide is a consequence of elec-
tron transfer chain disruption by excessive calcium concentrations
causing free electrons to react with oxygen, overwhelming the
superoxide dismutase system under ischemic conditions. Auto-
oxidation of oxyhemoglobin (OxyHb) in the CSF releases superox-
ide anion and hydrogen peroxide, which is then catalyzed by iron
released from OxyHb to form hydroxyl radical. These strong oxi-
dizing agents result in signifi cant lipid, protein and DNA damage
(
31
), leading to cellular apoptosis, endothelial injury, and BBB per-
meability (
32, 33
). OyxHb has also been shown to induce the
expression of R-type voltage-dependent calcium channels in cere-
bral arteries (
34
), which contributes to increased vessel constriction
following SAH (
35
).
Accumulation of intracellular calcium activates several enzymes
leading to additional free radical production; these include NOS,
xanthine oxidase (XO), and phospholipases. The neuronal and
inducible isoforms of NOS are upregulated in SAH, and the overall
effect of these enzymes is debated. It is hypothesized that nitrogen
oxide (NO) radical may play different temporal roles as ischemia
develops and matures. NO augments CBF via vasodilation in the
acute phase of injury, while 6 h post-SAH this effect is lessened and
NO becomes a contributor to cellular damage by creating addi-
tional oxidation (
11
).
Apoptosis has been observed in the hippocampus, BBB and vascu-
lature (
27, 28
), after aneurysm rupture. Several apoptotic path-
ways are implicated in SAH: the death receptor pathway,
caspase-dependent and independent pathways, as well as the mito-
chondrial pathway (
36
). SAH is thought to activate the death
receptor pathway primarily via the tumor necrosis factor receptors
(TNFR). Tumor necrosis factor alpha (TNF-
4.2. Signaling
Pathways Involved
in Early Brain Injury
) is upregulated fol-
lowing SAH and thought to activate internal apoptotic cascades via
p53 and Fas ligand (
37
). Recent evidence also suggests a role for
p53 in a caspase-independent pathway, acting through the mito-
chondrial protein apoptosis-inducing factor. The caspase indepen-
dent and dependent pathways are both mediated via the pro-death
Bcl-2 family of proteins.
The primary consequence of acute apoptotic cascades is mani-
fested in exacerbation of BBB disruption. This had been observed
in a biphasic pattern (
38
) resulting fi rst from the immediate physi-
ologic disruptions (
39
) and second from endothelial apoptosis
(
40
). Activation of the vascular endothelial growth factor (VEGF)
and consequently the MAP kinase pathway contributes to early
brain injury, and inhibition results in reduced brain edema, BBB
disruption and mortality (
41
). The Akt/GSK3
α
survival signal is
activated in cortical neurons following SAH and interference of
Akt phosphorylation increases neuronal injury (
42
).
β
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