Ischemic tolerance following low dose NMDA involves modulation of cellular stress proteins.

Abstract

Mild NMDA receptor activation is correlated with neuroprotection in models of cerebral ischemia. Neuroprotection with NMDA manifests as a form of ischemic tolerance and involves the induction of cellular stress systems sensitive to disturbances in cellular calcium homeostasis. Unilateral micro-injection of 10, 160 and 320 microM NMDA into the prefrontal cortex of a rat 30 min prior to permanent occlusion of the middle cerebral artery (MCAO) significantly reduced the area of infarct observed after 4 h of ischemia. The highest dose of NMDA (320 microM) prevented the propagation of ischemic damage through a direct toxicity on neuronal tissue adjacent to the injection site as demonstrated in thionin-stained sections. As a result, the degree of ischemia-induced damage was similar to that measured in rats pretreated with the low dose of NMDA (10 microM). Expression of heat shock protein (HSP) 70 and glucose-regulated protein (GRP) 94 in cortical samples taken from the region of infarct following MCAO was significantly reduced in rats pretreated with 10 microM NMDA compared to saline-injected control rats and rats pretreated with higher doses of NMDA. Furthermore, 10 microM NMDA did not appear to influence expression of m-calpain or GRP78, however, higher doses of NMDA did significantly induce expression of both proteins as assessed by Western blotting. In summary, our data demonstrate an in vivo rodent model of ischemic tolerance in which 30 min of neuronal preconditioning with 10 microM NMDA confers protection against a 4 h period of MCAO-induced ischemia. This effect may involve modulation of cellular stress signals, in particular HSP70 and GRP94.

• Authors: Monique C Saleh, Barry J Connell, Tarek M Saleh
• Journal: Brain research (Brain Res) Vol. 1247 Pg. 212-20 (Jan 09 2009) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 18992720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Agonists
• GRP78 protein, rat
• HSP70 Heat-Shock Proteins
• Heat-Shock Proteins
• Membrane Proteins
• Molecular Chaperones
• Neuroprotective Agents
• glucose-regulated proteins
• N-Methylaspartate
• Calpain

Topics

• Animals
• Brain (drug effects, metabolism, physiopathology)
• Calpain (drug effects, metabolism)
• Cytoprotection (drug effects, physiology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agonists (pharmacology, therapeutic use)
• HSP70 Heat-Shock Proteins (drug effects, metabolism)
• Heat-Shock Proteins (drug effects, metabolism)
• Hypoxia-Ischemia, Brain (drug therapy, metabolism, physiopathology)
• Infarction, Middle Cerebral Artery (drug therapy, metabolism, physiopathology)
• Ischemic Preconditioning (methods)
• Male
• Membrane Proteins (drug effects, metabolism)
• Molecular Chaperones (drug effects, metabolism)
• N-Methylaspartate (pharmacology, therapeutic use)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Prefrontal Cortex (drug effects, metabolism, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Stress, Physiological (drug effects, physiology)