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(Stroke. 2007;38:665.)
© 2007 American Heart Association, Inc.

Glutamate-Independent Calcium Toxicity: Introduction

Transient Receptor Potential Channels of the Melastatin Family and Ischemic Responses of Central Neurons

John F. MacDonald, PhD Michael F. Jackson, PhD

From the Department of Physiology, University of Toronto, Toronto, Canada.

Correspondence to John F. MacDonald, Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5T 1A8, Canada.

Abstract

The excitotoxic theory of stroke, which implicated N-methyl-D-aspartate (NMDA) receptors as mediators of excessive Ca²⁺ entry and neuronal death, generated a great deal of enthusiasm for the prospect of using NMDA receptor antagonists to prevent the associated brain injury. Unfortunately, these receptor antagonists failed to provide effective treatments for human stroke. In part, the failure is likely a consequence of having to administer these drugs within a very short therapeutic window after stroke and to the intolerable psychomimetic side effects associated with their use. However, new possibilities for therapeutic intervention are revealing themselves as our understanding of excitotoxicity evolves. We now recognize that ischemia and Ca²⁺ toxicity in central neurons can be attributed to a variety of mechanisms recruited downstream of NMDA receptor activation. These include the activation of Ca²⁺-permeable transient receptor potential channels of the melastatin family. The more-delayed activation of these channels offers the tantalizing possibility that drugs targeting selected members of this family may possess a wider therapeutic window for preventing the debilitating consequences after stroke onset.

Key Words: brain ischemia