title: Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats.
abstract: Melatonin, a natural product of the pineal gland, has been shown to protect against ischemic stroke, but the molecular mechanisms underlying its protective function are not fully understood. In the present study, we tested whether melatonin could protect against ischemia-reperfusion (I/R) injury to rat brain by targeting the autophagy pathway. The I/R brain injury was induced by the established rat transient middle cerebral artery occlusion model. We found intraperitoneal injection of melatonin can ameliorate rat brain injury as evidenced by multiple morphological and behavioral criteria, such as infarct size, neurological score, serum creatine kinase, and lactate dehydrogenase content, as well as pyknotic-positive cells. Further studies revealed that the beneficial effects of melatonin is through targeting the autophagy pathway by inhibiting expression of beclin-1 and conversion of LC3, as well as activating the PI3K/Akt pro-survival pathway. To further confirm this finding, the autophagy pathway was activated by lentiviral mediated beclin-1 delivery and the PI3K/Akt pathway was inhibited by a pharmacological inhibitor, LY294002. In both manipulations, the beneficial effects of melatonin were greatly abolished. Taken together, our study suggested melatonin plays a protective role against I/R brain injury by inhibiting autophagy and activating the PI3K/Akt pro-survival pathway.
authors.affiliation: Research Center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, China.
authors.forename: Yongqiu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jincai
authors.initials: J
authors.lastname: Hou
authors.forename: Jianxun
authors.initials: J
authors.lastname: Liu
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Yao
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D000071186:Beclin-1; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007274:Injections, Intraperitoneal; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D008550:Melatonin; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat