Amplification of inhibitory mechanisms in cerebral ischemia: an alternative approach to neuronal protection

Abstract

The central nervous systern consumes 20% of the cardiac output for normal function. The neurons are very sensitive to the effects of ischemia. Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular calcium (ca2+) buildup, relative lack of inhibitory responses, generation of oxygen free radicals (especially during the reperfusion period) and severa1 other destructive cascades. Medications that antagonize the effects of glutamate at post-synaptic receptors are either ineffective or have serious sideeffects. ca2+ entry blockers have shown disappointing results in clinical trials in patients with acute cerebral infarction. Data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 hours after the ischemic insult. Many such rnedications have few side-effects and are in clinical use for other indications. This review will surnmarize inhibitory rnechanisms that may be important in cerebral ischernia, and provide experimental evidence for their potential efficacy.