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Nitric Oxide in Brain Ischemia/Reperfusion Injury

  • Chapter
Book cover Nitric Oxide

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 143))

Abstract

The brain is a highly energetic organ, which requires a continuous supply of nutrients and oxygen from the circulatory system in order to function properly. Cessation of the blood supply to the brain for even a few minutes results in neuronal injury following initiation of a cascade of secondary mechanisms. Ischemia results in the reduction of resting membrane potential of glia and neurons in the brain. The leakage of potassium out of cells results in the depolarization of neurons, leading to a massive release of glutamate. Glutamate elicits its actions by acting on series of post-synaptic receptors, including the N-methyl-D-aspartate receptor (NMDA), non-NMDA receptors, and metabotropic glutamate receptors (SAMDANI et al. 1997). For nearly two decades, the actions of glutamate have been linked as important mediators of ischemic brain injury. The observation that activation of NMDA receptors generates nitric oxide (NO) in a calcium-dependent manner (GARTHWAITE et al. 1988; BREDT and SNYDER 1989; GARTHWAITE et al. 1989) raised the possibility that NO might be an important mediator in regulating glutamate neurotoxicity. The observation that non-selective NO synthase (NOS) inhibitors could reduce glutamate neurotoxicity in vitro (DAWSON et al. 1991b) and reduce infarct volume following transient focal ischemia in mice (NOWICKI et al. 1991) suggested a role for NO as a neurotoxin. Immediately, there was controversy over the role of NO in neurotoxicity and ischemic damage (DAWSON et al. 1994a; DAWSON and DAWSON 1996). Since then, a large body of scientific literature has evolved describing the role of NO in glutamate toxicity and ischemia-reperfusion injury. The early controversies were due to the important but opposing effects of NO generated from different NOS isoforms in the central nervous system (CNS), the use of nonselective NOS inhibitors, and the lack of understanding of the complex chemistry of NO in a biologic setting. Advances in pharmacology and chemistry, in addition to the generation of genetically engineered mice, have greatly expanded our understanding of NO biology in ischemic injury.

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Authors
  1. M. Sasaki
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  2. T. M. Dawson
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  3. V. L. Dawson
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Editor information

Editors and Affiliations

  1. Department of Pharmacology and Toxicology, Karl-Franzens-University of Graz, Universitätsplatz 2, 8010, Graz, Austria

    Bernd Mayer

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© 2000 Springer-Verlag Berlin Heidelberg

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Sasaki, M., Dawson, T.M., Dawson, V.L. (2000). Nitric Oxide in Brain Ischemia/Reperfusion Injury. In: Mayer, B. (eds) Nitric Oxide. Handbook of Experimental Pharmacology, vol 143. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-57077-3_24

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  • DOI: https://doi.org/10.1007/978-3-642-57077-3_24

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63026-2

  • Online ISBN: 978-3-642-57077-3

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