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: Xue-Mei Zhang, Li Zhang, Guili Wang, Wenxiu Niu, Zhijie He, Li Ding, Jie Jia
• Journal: Neurochemistry international (Neurochem Int) Vol. 90 Pg. 1-8 (Nov 2015) ISSN: 1872-9754 [Electronic] England
• PMID: 26116440 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Neuroprotective Agents
• Protein Kinase Inhibitors
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Autophagy (drug effects)
• Brain Ischemia (metabolism)
• Disease Models, Animal
• Male
• Mitochondria (drug effects, metabolism)
• Mitochondrial Dynamics (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism)
• Stroke (drug therapy, metabolism)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)