Focal Cerebral Ischemia and Reperfusion Induce Brain Injury Through α2δ-1–Bound NMDA Receptors. Issue 10 (October 2018)

• Record Type: Journal Article
• Authors: Luo, Yi; Ma, Huijie; Zhou, Jing-Jing; Li, Lingyong; Chen, Shao-Rui; Zhang, Jixiang; Chen, Lin; Pan, Hui-Lin
• Is Part Of: Stroke. Volume 49:Issue 10(2018)
• Publication Date: 2018-10
• Subjects: brain -- ischemia -- caspase -- 3 -- gabapentin -- hippocampus -- neurons -- NMDA receptor -- pregabalin; Cerebrovascular disease -- Periodicals; Cerebral circulation -- Periodicals; 616.81
• DOI: 10.1161/STROKEAHA.118.022330
• Languages: English
• ISSNs: 0039-2499

Abstract

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. α2δ-1 (encoded by Cacna2d1 ) is strongly expressed in many brain regions. We determined the contribution of α2δ-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 α2δ-1 protein glycosylation in the cerebral cortex, hippocampus, and striatum. Coimmunoprecipitation showed that ischemia rapidly enhanced the α2δ-1–NMDAR physical interaction in the mouse brain tissue. Inhibiting α2δ-1 with gabapentin, uncoupling the α2δ-1–NMDAR interaction with an α2δ-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 α2δ-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—: α2δ-1 is essential for brain ischemia–induced neuronal NMDAR hyperactivity, and α2δ-1–bound NMDARs mediate brain damage caused by cerebral ischemia. Targeting α2δ-1–bound NMDARs, without impairing physiological α2δ-1–free NMDARs, may be a promising strategy for treating ischemic stroke. Abstract : Supplemental Digital Content is available in the text.