In addition to the size of the stroke, its location, and the relative involvement of gray versus white matter are key determinants of outcome. For example, small white matter strokes often cause extensive neurologic deficits by interrupting the passage of large axonal bundles such as those within the internal capsule. Blood flow in white matter is lower than in gray matter, and white matter ischemia is typically severe, with rapid cell swelling and tissue edema because there is little collateral blood supply in deep white matter. Moreover, cells within the gray and white matter have different susceptibilities to ischemic injury. Amongst the neuronal population, well-defined subsets (the CA1 hippocampal pyramidal neurons, cortical projection neurons in layer 3, neurons in dorsolateral striatum, and cerebellar Purkinje cells) are particularly susceptible and undergo selective death after transient global cerebral ischemia . The major cell types composing the neurovascular module within white matter include the endothelial cell, perinodal astrocyte, axon, oligodendrocyte, and myelin. In general, oligodendrocytes are more vulnerable than astroglial or endothelial cells.
There are important differences in the pathophys-iology of white matter ischemia as compared to that of gray matter, which have implications for therapy . In the case of excitotoxicity, since the white matter lacks synapses, neurotransmitter release from vesicles does not occur despite energy depletion and neurotransmitter accumulation. Instead, there is reversal of Na+-dependent glutamate transport , resulting in glutamate toxicity with subsequent AMPA receptor activation, and excessive accumulation of calcium, which in turn activates calcium-dependent enzymes such as calpain, phospholipases, and protein kinase C, resulting in irreversible injury. The distinct lack of AMPA receptors expressing calci um-impermeable GluR2 subunits may make Oligodendroglia particularly vulnerable to excitotoxic injury . In the case of oxidative stress-induced white matter injury, the severity of injury appears to be greater in large axons as compared to small axons , although the mechanisms underlying these differences need further study. Despite these differences between gray and white matter injury, several common cascades of injury do exist. Damaged oligodendrocytes express death signals such as TNF and Fas ligand, and recruit caspase-mediated apoptotic-like pathways . Degradation of myelin basic protein by matrix metalloproteinases (MMPs) , and upregulation of MMPs in autopsied samples from patients with vascular dementia  suggest that proteolytic pathways are also recruited in white matter. These pathways might serve as common targets for stroke therapy.
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