Research Papers: Pathology:
Pannexin1 knockout and blockade reduces ischemic stroke injury in female, but not in male mice
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Moises Freitas-Andrade1,2, John F. Bechberger1, Brian A. MacVicar2, Victor Viau1 and Christian C. Naus1
1 Department of Cellular and Physiological Sciences, The Life Science Institute, University of British Columbia, Vancouver, British Columbia, Canada
2 Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
Christian C. Naus, email:
Keywords: stroke, neuroprotection, neuroinflammation, sex-differences, pannexin, Pathology Section
Received: December 15, 2016 Accepted: March 22, 2017 Published: April 07, 2017
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 (~ 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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