Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus.

Abstract

Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK-801. Further work revealed that the NR2A-type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A-preferring antagonist (NVP-A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B-preferring antagonist (Ro25) was without effect. Post C significantly up-regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca(2+) influx and activation/phosphorylation of CamKIIα at Thr(286), effects that were NR2A mediated as they were blocked by NVP-A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB-dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP-A. Taken as a whole, the current study provides evidence that NR2A-activation and downstream prosurvival signaling is a critical mediator of Post C-induced neuroprotection and cognitive enhancement following GCI.

• Authors: Xi Zhang, Quanguang Zhang, Jingyi Tu, Ying Zhu, Fang Yang, Bin Liu, Darrell Brann, Ruimin Wang
• Journal: Hippocampus (Hippocampus) Vol. 25 Issue 3 Pg. 286-96 (Mar 2015) ISSN: 1098-1063 [Electronic] United States
• PMID: 25271147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• 5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione
• Neuroprotective Agents
• Phenols
• Piperidines
• Quinoxalines
• Receptors, N-Methyl-D-Aspartate
• Ro 25-6981
• Dizocilpine Maleate
• CREB-Binding Protein
• Calcium
• N-methyl D-aspartate receptor subtype 2A

Topics

• Analysis of Variance
• Animals
• Brain Ischemia (complications, metabolism, pathology, therapy)
• CREB-Binding Protein (metabolism)
• Calcium (metabolism)
• Dizocilpine Maleate (therapeutic use)
• Hippocampus (drug effects, metabolism, pathology)
• Immunoprecipitation
• Male
• Maze Learning (drug effects)
• Neuroprotective Agents (therapeutic use)
• Phenols (therapeutic use)
• Piperidines (therapeutic use)
• Quinoxalines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Signal Transduction (drug effects, physiology)
• Time Factors