Introduction

Cerebral ischemic injury is the end product of a multitude of pathogenic factors acting in a coordinated fashion. Thus ionic and chemical changes, initiated by ischemia-induced energy failure, lead to a wide variety of biochemical and genomic effects that ultimately result in tissue damage (Figure 4.1) (reviewed by ref. 2). These biochemical and molecular events are associated with marked cellular changes (reviewed by ref. 3). While neurons and glia develop swelling, circulating white cells adhere to cerebral endothelial cells and invade the brain parenchyma. Furthermore, astrocytes and microglia become activated, while macrophages accumulate in the injured areas. Invasion of the brain tissue by blood-borne white cells and the activation of microglia contribute to the development of brain damage. However, the mechanisms by which these inflammatory cells exert their deleterious effects are not well understood. Evidence accumulated over the past several years suggests that nitric oxide (NO) and cyclooxygenase (COX) products are involved in the mechanisms by which postischemic inflammation contributes to ischemic brain injury. In this chapter, this evidence will be reviewed and discussed in the context of the interactions between NO produced by inducible nitric oxide synthase (iNOS) and COX-2.

Neuromodulatory and neurotoxic actions of nitric oxide

NO is a molecular mediator that is synthesized by the enzyme NOS from l-arginine. Three isoforms of NOS have been described: neuronal NOS (nNOS), endothelial NOS (eNOS), and iNOS.