title: Reversible cyclosporin A-sensitive mitochondrial depolarization occurs within minutes of stroke onset in mouse somatosensory cortex in vivo: a two-photon imaging study.
abstract: Neuronal structure and function are rapidly damaged during global ischemia but can in part recover during reperfusion. Despite apparent recovery in the hours/days following an ischemic episode, delayed cell death can be initiated, making it important to understand how initial ischemic events affect potential mediators of apoptosis. Mitochondrial dysfunction and the opening of the mitochondrial permeability transition pore (mPTP) are proposed to link ischemic ionic imbalance to mitochondrially mediated cell death pathways. Using two-photon microscopy, we monitored mitochondrial transmembrane potential (Deltapsi(m)) in vivo within the somatosensory cortex during ischemia and reperfusion in a mouse global ischemia model. Our results indicated a synchronous loss of Deltapsi(m) within 1-3 min of ischemic onset that was linked to within seconds of plasma membrane potential (Deltapsi(p)) depolarization. Deltapsi(m) recovered rapidly upon reperfusion, and no delayed depolarization was observed over 2 h. Cyclosporin A treatment largely blocked Deltapsi(m) collapse during ischemia, suggesting a role for the mPTP. Blocking Deltapsi(m) depolarization did not affect structural damage to dendrites, indicating that the opening of the mPTP and damage to dendrites are separable pathways that are activated during Deltapsi(p) depolarization. Our findings using in vivo imaging suggest that mitochondrial dysfunction and specifically the activation of the mPTP are early reversible events during brain ischemia that could trigger delayed cell death.
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Ran R
authors.initials: RR
authors.lastname: Liu
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: thmurphy@interchange.ubc.ca.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015427:Reperfusion Injury / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine