Prevention of Cyclophilin D-Mediated mPTP Opening Using Cyclosporine-A Alleviates the Elevation of Necroptosis, Autophagy and Apoptosis-Related Markers Following Global Cerebral Ischemia-Reperfusion.
The mitochondrial permeability transition pore (mPTP) is a complex channel of the inner membrane, the opening of which leads to mitochondrial swelling and dissipation of mitochondrial membrane potential (MMP). Here, we aimed to evaluate the role of the cyclophilin D (CypD) as a prominent mediator of mPTP, on necroptosis and autophagy as well as apoptosis, beyond the global cerebral ischemia-reperfusion (I/R) injury. We showed that while cerebral I/R injury is accompanied by loss of MMP, mitochondrial swelling and programmed cell death, pretreatment with cyclosporine-A (CsA) as a potent inhibitor of CypD, led to partial but significant reduction in necroptosis markers, RIP1 and RIP3 as well as activity of glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1), downstream enzymes of RIP3. Administration of CsA also partially decreased autophagy associated proteins. Furthermore, we demonstrated that Bax/Bcl-2 ratio as well as caspase-3 activation, as the executioner of apoptosis, noticeably decreased by CsA pretreatment. Taken together, our results suggest that the CypD alongside the apoptosis regulation plays a partial role in inducing necroptosis and autophagy.
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Farinoosh
F
Fakharnia
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Fariba
F
Khodagholi
NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Leila
L
Dargahi
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. aahmadiani@yahoo.com.
Abolhassan
A
Ahmadiani
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002540:Cerebral Cortex / Q000098:blood supply*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*
D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D005969:Glutamate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat; D021983:Cyclophilins; D005974:Glutamate-Ammonia Ligase
Apoptosis; Autophagy; Cerebral ischemia-reperfusion; Cyclosporine-A; Necroptosis; mPTP
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