Excitotoxicity and Ionic Imbalance

Ischemic stroke results in impaired cellular energy metabolism and failure of energy-dependent processes such as the sodium-potassium ATPase. Loss of energy stores results in ionic imbalance, neurotrans-mitter release, and inhibition of the reuptake of excitatory neurotransmitters such as glutamate. Glutamate binding to ionotropic N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxa-zolepropionic acid (AMPA) receptors promotes excessive calcium influx that triggers a wide array of downstream phospholipases and proteases, which in turn degrade membranes and proteins essential for cellular integrity. In experimental models of stroke, extracellular glutamate levels increase in the micro-dialysate [2, 3], and glutamate receptor blockade attenuates stroke lesion volumes. NMDA receptor antagonists prevent the expansion of stroke lesions in part by blocking spontaneous and spreading depolarizations of neurons and glia (cortical spreading depression) [4]. More recently, activation of the metabotropic subfamily of receptors has been implicated in glutamate excitotoxicity [5].

Up- and downregulation of specific glutamate receptor subunits contribute to stroke pathophysiology in different ways [6]. For example, after global cerebral ischemia, there is a relative reduction of calcium-

impermeable GluR2 subunits in AMPA-type receptors, which makes these receptors more permeable to deleterious calcium influx [7]. Antisense knockdown of calcium-impermeable GluR2 subunits significantly increased hippocampal injury in a rat model of transient global cerebral ischemia, confirming the importance of these regulatory subunits in mediating neuronal vulnerability [8]. Variations in NMDA receptor subunit composition can also have an impact on tissue outcome. Knockout mice deficient in the NR2A subunit show decreased cortical infarction after focal stroke [9]. Medium spiny striatal neurons, which are selectively vulnerable to ischemia and ex-citotoxicity, preferentially express NR2B subunits [10]. Depending upon the subtype, metabotropic glutamate receptors can trigger either pro-survival or pro-death signals in ischemic neurons [5]. Understanding how the expression of specific glutamate receptor subunits modifies cell survival should stimulate the search for stroke neuroprotective drugs that selectively target specific subunits.

Ionotropic glutamate receptors also promote perturbations in ionic homeostasis that play a critical role in cerebral ischemia. For example, L-, P/Q-, and N-type calcium channel receptors mediate excessive calcium influx, and calcium channel antagonists reduce ischemic brain injury in preclinical studies [11-13]. Zinc is stored in vesicles of excitatory neurons and co-released upon depolarization after focal cerebral ischemia, resulting in neuronal death [14, 15]. Recently, imbalances in potassium have also been implicated in ischemic cell death. Compounds that selectively modulate a class of calcium-sensitive high-conductance potassium (maxi-K) channels protect the brain against stroke in animal models [16].

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