Journal
ONCOTARGET
Volume 8, Issue 23, Pages 36973-36983Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16937
Keywords
stroke; neuroprotection; neuroinflammation; sex-differences; pannexin; Pathology Section
Categories
Funding
- Heart and Stroke Foundation of Canada MFA, through the support of Brain Canada
- Health Canada
- Michael Smith Foundation for Health Research
- Genome BC
- Pacific Alzheimer's Research Foundation (CCN)
- Canadian Institutes of Health Research (CIHR) [148397, 8545, 115121, 136856]
- CIHR Team [R1478A47]
- CCN
- BAM
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The membrane channel Pannexin 1 (Panx1) mediates apoptotic and inflammatory signaling cascades in injured neurons, responses previously shown to be sexually dimorphic under ischemic conditions. We tested the hypothesis that Panx1 plays an underlying role in mediating sex differences in stroke outcome responses. Middle-aged, 8-9 month old male and female wild type and Panx1 KO mice were subjected to permanent middle cerebral artery (MCA) occlusion, and infarct size and astrocyte and microglia activation were assessed 4 days later. The sexually dimorphic nature of Panx1 deletion was also explored by testing the effect of probenecid a known Panx1 blocker to alter stroke volume. Panx1 KO females displayed significantly smaller infarct volumes (similar to 50 % reduction) compared to their wild-type counterparts, whereas no such KO effect occurred in males. This sex-specific effect of Panx1 KO was recapitulated by significant reductions in peri-infarct inflammation and astrocyte reactivity, as well as smaller infarct volumes in probenecid treated females, but not males. Finally, females showed overall, higher Panx1 protein levels than males under ischemic conditions. These findings unmask a deleterious role for Panx1 in response to permanent MCA occlusion, that is unique to females, and provide several new frameworks for understanding sex differences in stroke outcome.
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