Acute Physiologic and Morphologic Assessment Following Subarachnoid Hemorrhage - Animal Models of Acute Neurological Injuries: Injury and Mechanistic Assessments - page 297

has been observed as early as 20 min following ischemic onset in
rodents ( 24 ) (Fig. 4 ). Upregulation of aquaporin protein channels
1 and 4 following SAH is thought to be involved in edema forma-
tion and elimination, recent evidence shows increased brain edema
in AQP-4 null mice at 6 h post-SAH ( 25 ). Maintenance of the
osmotic homeostasis between the intra- and extracellular compart-
ments is disrupted, causing a cytotoxic environment.

4. Metabolic
Failure and Cell
Death

The absence of oxygen causes transition from aerobic mitochon-
drial respiration and ATP production to anaerobic glycolysis. This
produces progressive acidosis due to the formation of lactic acid
and an increase in free radical production, while increased gluta-
mate and anoxic depolarization cause excitotoxicity. These cascades
result in proteolysis, lipolysis, DNA damage, and ultimately neu-
ronal loss ( 11 ). Necrosis develops in areas of critical ischemia while
the neighboring penumbral region is affected by free radical pro-
duction, toxic metabolites, and spreading depolarizations ( 26 )
(Fig. 5 ), leading to a spectrum of apoptosis to necrosis dependent
upon degree of ischemic insult. The vasculature and circumven-
tricular regions are particularly susceptible to necrosis following
SAH ( 27, 28 ). The focus of scientifi c and clinical investigation has
been on discovery of novel therapies to promote survival of the
penumbral tissue by targeting cell survival pathways.

4.1. Oxidative Stress

The homeostasis of reactive oxygen species (ROS) production
and their neutralization by intrinsic antioxidant systems is upset

Fig. 5. Cortical Spreading Depolarizations and Ischemia in SAH patient. This fi gure shows a temporal cluster of four depo-
larizations spontaneously recurring within a 3 hr period. Each depolarization, measured as a 10-20 mV negative shift in
direct current electrocorticography (DCECoG; Hartings et al., 2009), is signifi cantly prolonged, evidencing limited energy
supply for tissue repolarization and a developing ischemic lesion. Cerebral blood fl ow measured by laser doppler fl owmetry
(LD-CBF) adjacent to the ECoG electrode shows pathologic 'inverse' neurovascular coupling, i.e. transient hypoperfusions
in place of the hyperemic response observed in normal cortex. Methods are described in Dreier et al., 2009. Figure cour-
tesy of JP Dreier (Berlin, Germany), JA Hartings (Cincinnati, OH), and T Watanabe (Silver Spring, MD).