Stroke: Mechanisms of Excitotoxicity and Approaches for Therapy
Authors: O'Neill Michael J. , Lodge David , McCulloch James 
Published: March 2007

Stroke is the third highest cause of mortality in industrialized countries. The majority of stroke patients survive the initial stroke but are left with a wide range of disability because of brain damage. The interruption of blood flow and energy production in a region of the brain is the initiating event for brain damage in stroke.

In the early 1980s there was a major investment in research into the mechanisms contributing to ischemic brain injury and possible approaches to protecting the brain from ischemic injury. These studies ranged from cultures of primary neurons in a dish to slice preparations and a number of rodent models of global and focal cerebral ischemia. Glutamate, the major excitatory amino acid in the central nervous system (CNS), emerged as a possible culprit, and application of glutamate analogues produced cell death, or “excitotoxicity,” in both in vitro and in vivo experimental situations. The levels of extracellular glutamate were also elevated in models of cerebral ischemia, and it was suggested that activation ofN‐methyl‐D‐aspartate (NMDA) receptors allowed a massive influx of Ca2+into postsynaptic cells and initiated immediate (or more rapid necroticlike) and slower secondary (or more apoptoticlike) events and subsequent cell death.

As research progressed, a multitude of additional signaling pathways were implicated, but these earlier studies had excited the pharmaceutical industry, and many companies started developing glutamate receptor antagonists in an attempt to prevent ischaemic injury. The earliest drugs were competitive and noncompetitive NMDA antagonists, and these molecules showed efficacy in a number of rodent models of focal cerebral ischemia. The molecules reduced the infarct volume (volume of brain damage) produced by middle cerebral artery occlusion (MCAO) in rats, mice, or cats when given before or immediately after occlusion. The middle cerebral artery is the major blood vessel that supplies the cortex, and occlusion of the vessel produces a regional “core” of damage with a surrounding area of “penumbra” where tissue is hypoperfused but in theory is still salvageable. Based on the preclinical data, many molecules progressed to clinical trials, but all were later abandoned due to poor side‐effect profiles or failure to meet the primary outcome criteria. There are many reasons that could explain the negative clinical data. Several other agents that act on upstream (sodium and calcium channel blockers) or downstream (nitric oxide synthase inhibitors, caspase inhibitors, antiinflammatory agents) pathways have also been evaluated preclinically.

In this chapter we will review the major pathways that have been implicated in ischemic injury and highlight the role of excitotoxicity in this process. We will also summarize the main pharmacological interventions that have been attempted and the approaches taken to neuroprotect the brain. We will briefly review the clinical data. A number of newer mechanisms and modifications in criteria required to progress putative neuroprotective agents will also be summarized. Finally, putative mechanisms to help repair/recover from acute brain injury will also be discussed. Despite setbacks from earlier clinical trials, acute brain injury from stroke and traumatic brain injury remains a major cause of mortality and disability and novel approaches to reduce brain injury or enhance recovery of function are desperately needed.