Journal
EXPERIMENTAL NEUROLOGY
Volume 296, Issue -, Pages 32-40Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2017.06.023
Keywords
Transient receptor potential melastatin 2; Ion channel; Hypoxic-ischemic brain injury; Neuroprotection; Glycogen synthase kinase 3 beta; Protein kinase B/Akt
Categories
Funding
- Heart and Stroke Foundation of Canada [G-13-0003069]
- Canadian Institutes of Health Research (CIHR) China-Canada Joint Health Research Initiative (CIHR) [132571]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2016-04574]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-06471]
- Queen Elizabeth II/Heart & Stroke Foundation of Ontario Graduate Scholarships in Science and Technology Award
- Ontario Graduate Scholarship
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Transient receptor potential melastatin 2 (TRPM2), a calcium-permeable non-selective cation channel, is reported to mediate brain damage following ischemic insults in adult mice. However, the role of TRPM2 channels in neonatal hypoxic-ischemic brain injury remains unknown. We hypothesize that TRPM2(+/-)and TRPM2(-/-)neonatal mice have reduced hypoxic-ischemic brain injury. To study the effect of TRPM2 on neonatal brain damage, we used 2,3,5-triphenyltetrazolium chloride (TTC) staining to assess the infarct volume and whole brain imaging to assess morphological changes in the brain. In addition, we also evaluated neurobehavioral outcomes for sensorimotor function 7 days following hypoxic-ischemic brain injury. We report that the infarct volumes were significantly smaller and behavioral outcomes were improved in both 7RPM2(+/-)and TRPM2(-/-)mice compared to that of wildtype mice. Next, we found that TRPM2-null mice showed reduced dephosphorylation of GSK-3 beta following hypoxic ischemic injury unlike sham mice. TRPM2(+/-)and TRPM2(-/-)mice also had reduced activation of astrocytes and microglia in ipsilaterel hemispheres, compared to wildtype mice. These findings suggest that TRPM2 channels play an essential role in mediating hypoxic-ischemic brain injury in neonatal mice. Genetically eliminating TRPM2 channels can provide neuroprotection against hypoxic-ischemic brain injury and this effect is elicited in part through regulation of GSK-3 beta. (C) 2017 Elsevier Inc. All rights reserved.
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