Focal Cerebral Ischemia and Reperfusion Induce Brain Injury Through ?2?-1-Bound NMDA Receptors.

ABSTRACT: Background and Purpose- Glutamate NMDARs (N-methyl-D-aspartate receptors) play a major role in the initiation of ischemic brain damage. However, NMDAR antagonists have no protective effects in stroke patients, possibly because they impair physiological functions of NMDARs. ?2?-1 (encoded by Cacna2d1) is strongly expressed in many brain regions. We determined the contribution of ?2?-1 to NMDAR hyperactivity and brain injury induced by ischemia and reperfusion. Methods- Mice were subjected to 90 minutes of middle cerebral artery occlusion followed by 24 hours of reperfusion. Neurological deficits, brain infarct volumes, and calpain/caspase-3 activity in brain tissues were measured. NMDAR activity of hippocampal CA1 neurons was measured in an in vitro ischemic model. Results- Middle cerebral artery occlusion increased ?2?-1 protein glycosylation in the cerebral cortex, hippocampus, and striatum. Coimmunoprecipitation showed that ischemia rapidly enhanced the ?2?-1-NMDAR physical interaction in the mouse brain tissue. Inhibiting ?2?-1 with gabapentin, uncoupling the ?2?-1-NMDAR interaction with an ?2?-1 C terminus-interfering peptide, or genetically ablating Cacna2d1 had no effect on basal NMDAR currents but strikingly abolished oxygen-glucose deprivation-induced NMDAR hyperactivity in hippocampal CA1 neurons. Systemic treatment with gabapentin or ?2?-1 C-terminus-interfering peptide or Cacna2d1 genetic knock-out reduced middle cerebral artery occlusion-induced infarct volumes, neurological deficit scores, and calpain/caspase-3 activation in brain tissues. Conclusions- ?2?-1 is essential for brain ischemia-induced neuronal NMDAR hyperactivity, and ?2?-1-bound NMDARs mediate brain damage caused by cerebral ischemia. Targeting ?2?-1-bound NMDARs, without impairing physiological ?2?-1-free NMDARs, may be a promising strategy for treating ischemic stroke.

SUBMITTER: Luo Y 

PROVIDER: S-EPMC6205748 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature