title: Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice.
abstract: Apart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it is not clear (i) whether increased PI3K/Akt phosphorylation is a concomitant event or it directly contributes to melatonin's neuroprotective effect, and (ii) how melatonin regulates PI3K/Akt signaling pathway after FCI. In this study, we showed that Akt was intensively phosphorylated at the Thr308 activation loop as compared with Ser473 by melatonin after FCI. Melatonin treatment reduced infarct volume, which was reversed by PI3K/Akt inhibition. However, PI3K/Akt inhibition did not inhibit melatonin's positive effect on brain swelling and IgG extravasation. Additionally, phosphorylation of mTOR, PTEN, AMPKα, PDK1 and RSK1 were increased, while phosphorylation of 4E-BP1, GSK-3α/β, S6 ribosomal protein were decreased in melatonin treated animals. In addition, melatonin decreased apoptosis through reduced p53 phosphorylation by the PI3K/Akt pathway. In conclusion, we demonstrated the activation profiles of PI3K/Akt signaling pathway components in the pathophysiological aspect of ischemic stroke and melatonin's neuroprotective activity. Our data suggest that Akt phosphorylation, preferably at the Thr308 site of the activation loop via PDK1 and PTEN, mediates melatonin's neuroprotective activity and increased Akt phosphorylation leads to reduced apoptosis.
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Medical Biology, Istanbul Medipol University, Turkey.
authors.forename: Ulkan
authors.initials: U
authors.lastname: Kilic
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Ahmet Burak
authors.initials: AB
authors.lastname: Caglayan
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Mustafa Caglar
authors.initials: MC
authors.lastname: Beker
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Mehmet Yalcin
authors.initials: MY
authors.lastname: Gunal
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Berrak
authors.initials: B
authors.lastname: Caglayan
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Yalcin
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Taha
authors.initials: T
authors.lastname: Kelestemur
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey.
authors.forename: Reyhan Zeynep
authors.initials: RZ
authors.lastname: Gundogdu
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Neurology, Istanbul Medipol University, Turkey.
authors.forename: Burak
authors.initials: B
authors.lastname: Yulug
authors.affiliation: Dept. of Physiology, Yeditepe University, Istanbul, Turkey.
authors.forename: Bayram
authors.initials: B
authors.lastname: Yılmaz
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Histology and Embryology, Istanbul Medipol University, Turkey.
authors.forename: Bilal Ersen
authors.initials: BE
authors.lastname: Kerman
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, Istanbul Medipol University, Turkey. Electronic address: kilic44@yahoo.com.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism; D008550:Melatonin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects; D013912:Threonine / Q000378:metabolism
chemical_list: D000975:Antioxidants; D007074:Immunoglobulin G; D008550:Melatonin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013912:Threonine; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C494929:PTEN protein, human
keywords: Brain injury; Melatonin; PI3K inhibition; PI3K/Akt signaling pathway