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Open AccessArticle

Assessing the Effects of Cytoprotectants on Selective Neuronal Loss, Sensorimotor Deficit and Microglial Activation after Temporary Middle Cerebral Occlusion

1
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1QQ, UK
2
Department of Neurology and Center for Stroke Research, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
3
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 1QQ, UK
4
Department of Pharmacology, School of Medicine, University of California Davis, Davis, CA 95817, USA
5
Department of Neurology, Sainte-Anne Hospital, INSERM U1266, Paris University,75014 Paris, France
*
Author to whom correspondence should be addressed.
Brain Sci. 2019, 9(10), 287; https://doi.org/10.3390/brainsci9100287
Received: 30 September 2019 / Revised: 18 October 2019 / Accepted: 20 October 2019 / Published: 22 October 2019
(This article belongs to the Collection Collection on Molecular and Cellular Neuroscience)
Although early reperfusion after stroke salvages the still-viable ischemic tissue, peri-infarct selective neuronal loss (SNL) can cause sensorimotor deficits (SMD). We designed a longitudinal protocol to assess the effects of cytoprotectants on SMD, microglial activation (MA) and SNL, and specifically tested whether the KCa3.1-blocker TRAM-34 would prevent SNL. Spontaneously hypertensive rats underwent 15 min middle-cerebral artery occlusion and were randomized into control or treatment group, which received TRAM-34 intraperitoneally for 4 weeks starting 12 h after reperfusion. SMD was assessed longitudinally using the sticky-label test. MA was quantified at day 14 using in vivo [11C]-PK111195 positron emission tomography (PET), and again across the same regions-of-interest template by immunofluorescence together with SNL at day 28. SMD recovered significantly faster in the treated group (p = 0.004). On PET, MA was present in 5/6 rats in each group, with no significant between-group difference. On immunofluorescence, both SNL and MA were present in 5/6 control rats and 4/6 TRAM-34 rats, with a non-significantly lower degree of MA but a significantly (p = 0.009) lower degree of SNL in the treated group. These findings document the utility of our longitudinal protocol and suggest that TRAM-34 reduces SNL and hastens behavioural recovery without marked MA blocking at the assessed time-points. View Full-Text
Keywords: selective neuronal loss; microglial activation; PET; ischemic stroke; KCa3.1; TRAM-34; reperfusion injury selective neuronal loss; microglial activation; PET; ischemic stroke; KCa3.1; TRAM-34; reperfusion injury
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Emmrich, J.V.; Ejaz, S.; Williamson, D.J.; Hong, Y.T.; Sitnikov, S.; Fryer, T.D.; Aigbirhio, F.I.; Wulff, H.; Baron, J.-C. Assessing the Effects of Cytoprotectants on Selective Neuronal Loss, Sensorimotor Deficit and Microglial Activation after Temporary Middle Cerebral Occlusion. Brain Sci. 2019, 9, 287.

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