Specific therapies

Attention has focused on the role of specific antagonists of excitatory neurotransmitters or inhibitors of intracellular events following episodes of loss of ionic homeostasis.

Ischemia results in the loss of normal mechanisms for release and uptake of excitatory neurotransmitters in the central nervous system. Glutamate and aspartate are implicated and mediate neuronal damage and cell death. Energy sources become exhausted during ischemia and the energy-dependent sodium pump fails. This leads to membrane depolarization due a sudden influx of Na + and Cl- and efflux of K+. Voltage-dependent Ca2+ channels are opened, allowing a massive influx of Ca2+ which causes a high intracellular Ca2+ concentration. This activates enzymes which disrupt receptor function and mitochondrial and cell membrane integrity. Membrane phospholipids can then be broken down to free fatty acids which are metabolized to prostaglandins, leukotrienes, and free radicals. Following this neurotoxic cascade, additional intracellular damage results from second-messenger activation which in turn activates protein kinase C and release of Ca 2+ from the endoplasmic reticulum.

W-Methyl-D-aspartate (NMDA) antagonists have been observed to reduce neuronal injury under a variety of experimental conditions. One such antagonist, dizocilpine, has been used in therapeutic studies, but initial encouraging results need to be substantiated. Glutamate AMPA-receptor antagonists improve outcome from global ischemia in animals even when given some time after the insult. However, major side-effects have made such compounds slow to enter the clinical field, although human trials are now under way.

Calcium entry into cells can be non-competitively antagonized by dihydropyridines such as nimodipine and nicardipine. These compounds are used for the prevention and treatment of vasospasm after subarachnoid hemorrhage but have little efficacy after global ischemia. Recent studies have failed to show improvement in outcome when nimodipine is given after head injury, except in subgroups of patients with subarachnoid blood. Interestingly, a combination of nimodipine and dizocilpine decreases neuronal damage in animal models of ischemia, presumably because of the overlapping effects of the two drugs on calcium influx.

Oxygen free radicals are generated in excess in ischemic brain and contribute significantly to further neuronal damage and death. Free-radical scavengers, such as superoxide dismutase and dihydrolipoate, may decrease mortality but do not improve outcome. A novel group of compounds have been designed which are potent inhibitors of lipid peroxidation induced by oxygen free radicals. One such drug, tirilazid, has shown some protective benefit in animal models of cerebral ischemia.

Nitric oxide may mediate ischemic cerebral damage. It is produced postsynaptically in response to activation by excitatory amino acids and then diffuses into presynaptic nerve endings, activating guanylate cyclase and thereby increasing levels of cGMP. Nitric oxide is also highly reactive in its own right, reacting with the superoxide anion to produce hydroxyl free radicals in the central nervous system. Nitric oxide synthesis may also play a part in cerebral flow-metabolism coupling and therefore be important in the local regulation of blood flow. Blockade of nitric oxide synthesis with WG-nitro-L-arginine reduces infarct size in animal models of ischemia.

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