title: Suppression of mitochondrial fission in experimental cerebral ischemia: The potential neuroprotective target of p38 MAPK inhibition.
abstract: In the present study, we investigated the neuroprotective role of p38 inhibition on experimental stroke in rats. p38 inhibition treatment alleviated the brain infarction volume and neurological deficits following ischemia, promoted the activation of Extracellular signal-regulated kinases (ERK1/2), suppressed the activation of Glycogen synthase kinase 3 beta (GSK3b). Application of two p38 inhibitors, both SB239063 and Losmapimod could down-regulate DLP1 and MFF, which were involved in mitochondrial fission and fragmentation. Losmapimod application progressively suppressed DLP1/MFF from 6 h to 24 h after ischemia-reperfusion injury. SB239063 pretreatment further showed the suppression of DLP1/MFF, and up-regulated the protein levels of p62 and Mitochondrial Complex I at 5 mg/kg dose. Our results suggested that inhibition of p38 MAPK attenuated mitochondrial fragmentation/mitophagy after ischemic attack. In conclusion, p38 inhibition treatment might promote cellular survival signaling pathways, attenuate mitochondrial autophagy to maintain mitochondrial contents. This study suggests a potential neuroprotective target of p38 inhibition via suppressing mitochondrial fragmentation/mitophagy in cerebral ischemic injury.
authors.affiliation: Department of Traditional Chinese and Western Medicine Combination, Henan Xinxiang Center Hospital, Henan Xinxiang 453000, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350108, China.
authors.forename: Guili
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Wenxiu
authors.initials: W
authors.lastname: Niu
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: shannonjj@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Jia
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Mitochondrial fission; Mitophagy; Neuroprotection; p38