Effect of Nitric Oxide Synthase Inhibitor on a Hyperglycemic Rat Model of Reversible Focal Ischemia: Detection of Excitatory Amino Acids Release and Hydroxyl Radical Formation

Brain Res. 1998 Apr 27;791(1-2):146-56. doi: 10.1016/s0006-8993(98)00089-4.

Abstract

The purpose of this study was to investigate the mechanisms by which a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), is neuroprotective in the hyperglycemic rat model of 2 h of transient middle cerebral artery occlusion followed by 2 h of reperfusion (MCAO/R). The salicylate trapping method was used in conjunction with a microdialysis technique to continuously estimate hydroxyl radical (.OH) formation by measurement of the stable adducts 2,3- and 2,5-dihydroxybenzoic acid (DHBA). Extracellular excitatory amino acids (EAAs) were detected from the same microdialysis samples. Magnetic resonance imaging (MRI) techniques were used to measure neuronal and cerebrovascular injury. The magnitude of EAA release correlated with the levels of the .OH adducts. Treatment with L-NAME (3 mg/kg, i.p.) 1 min before MCAO, and again 1 min before reperfusion, reduced the levels of DHBA by 46. 4% and glutamate by 50.5% in the hyperglycemic rats compared to untreated hyperglycemic controls. MRI indicated that L-NAME reduced the no-reflow zone and the cytotoxic lesion volume to 22.5% and 21. 0%, respectively, that of hyperglycemic controls. Co-treatment with the nitric oxide (NO) donor L-arginine completely eliminated the protective effects of l-NAME with respect to .OH and EAA levels as well as MRI lesion volume. Our data suggest that hyperglycemic MCAO/R results in excessive glutamate excitotoxicity, leading to enhanced generation of .OH via a NO-mediated mechanism, in turn resulting in severe ischemia/reperfusion brain injury.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Citrulline / metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / therapeutic use*
  • Glutamic Acid / metabolism
  • Hydroxyl Radical
  • Hyperglycemia / complications
  • Hyperglycemia / metabolism*
  • Ischemic Attack, Transient / complications
  • Ischemic Attack, Transient / drug therapy*
  • Ischemic Attack, Transient / metabolism
  • Magnetic Resonance Imaging
  • Male
  • NG-Nitroarginine Methyl Ester / therapeutic use*
  • Neuroprotective Agents / therapeutic use*
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Citrulline
  • Hydroxyl Radical
  • Glutamic Acid
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester