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Endothelin-1-mediated cerebral ischemia in mice: early cellular events and the role of caspase-3

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Abstract

Over the past 30 years a number of animal models of cerebral ischemic injury have been developed. Middle cerebral artery occlusion (MCAO) in particular reproduces both ischemic and reperfusion elements and is widely utilized as a model of ischemic stroke in rodents. However substantial variability exists in this model even in clonal inbred mice due to stochastic elements of the cerebral vasculature. Models such as MCAO thus exhibit significant irreducible variabilities with respect to their zone of injury as well as inducing a sizable volume of injury to the cerebrum with damage to sub-cortical structures, conditions not typically seen for the majority of human clinical strokes. An alternative model utilizes endothelin-1 application focally to cerebral vasculature, resulting in an ischemic reperfusion injury which more closely mimics that seen in human clinical stroke. In order to further define this model we demonstrate that intra-cortical administration of ET-1 results in a highly reproducible pattern of tissue injury which is limited to the cerebral cortex, characterizing the early cellular and molecular events which occur during the first 24 h post-injury. In addition we demonstrate that caspase-3 is both necessary and sufficient to regulate a majority of cortical cell death observed during this period. The enhanced survival effects seen upon genetic deletion of caspase-3 appear to arise as a result of direct modification of cell autonomous PCD signaling as opposed to secondary effectors such as granulocyte infiltration or microglia activation. Taken together these findings detail the early mechanistic features regulating endothelin-1-mediated ischemic injury.

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Acknowledgements

We would like to thank Kyle Gill and Ryan Harrietha for genotyping assistance; Zoe Winterton-Perks for assistance with histology; Zhihua Huang and Lida Du for assistance with TTC staining; and Ali Darbandi and Doug Holmyard for electron microscopy assistance.

Funding

This study has been funded by grants awarded to J.H. from Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN 298553-12) and Heart and Stroke Society of Canada (72043506). C.D.S. additionally received scholarship funding from Natural Sciences and Engineering Research Council of Canada (NSERC) and Queen Elizabeth II Graduate Scholarships in Science & Technology- Merck Company of Canada.

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  1. Department of Pharmaceutical Sciences, University of Toronto, 144 College St. Rm 962, Toronto, ON, M5S 3M2, Canada

    Chesarahmia Dojo Soeandy, Faraz Salmasi, Maya Latif, Nan Ji Suo & Jeffrey T. Henderson

  2. Princess Margaret Cancer Center, University Health Network, 610 University Avenue Rm 7-323, Toronto, ON, M5G 2C1, Canada

    Andrew J. Elia

  3. Department of Medical Biophysics, University of Toronto, 101 College Street Rm 15-701, Toronto, ON, M5G 1L7, Canada

    Andrew J. Elia

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  1. Chesarahmia Dojo Soeandy
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Correspondence to Jeffrey T. Henderson.

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Dojo Soeandy, C., Salmasi, F., Latif, M. et al. Endothelin-1-mediated cerebral ischemia in mice: early cellular events and the role of caspase-3. Apoptosis 24, 578–595 (2019). https://doi.org/10.1007/s10495-019-01541-z

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