Ology, Istanbul Medipol University, Turkey e Dept. of Histology and Embryology
Ology, Istanbul Medipol University, Turkey e Dept. of Histology and Embryology, Istanbul Medipol University, Turkey f Dept. of Physiology, Yeditepe University, Istanbul, Turkeyb cA R T I C L E I N F OKeywords: PI3K/Akt signaling Cadherin-11 Protein site pathway PI3K inhibition Melatonin Brain injuryA B S T R A C TApart from its potent antioxidant property, recent studies have revealed that melatonin promotes PI3K/Akt phosphorylation following focal cerebral ischemia (FCI) in mice. However, it truly is not clear (i) irrespective of whether enhanced PI3K/Akt phosphorylation is actually a concomitant event or it directly contributes to melatonin’s neuroprotective impact, 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 right after FCI. Melatonin treatment reduced infarct volume, which was reversed by PI3K/Akt inhibition. On the other hand, PI3K/Akt inhibition didn’t inhibit melatonin’s good effect on brain swelling and IgG extravasation. Also, phosphorylation of mTOR, PTEN, AMPK, PDK1 and RSK1 were improved, whilst phosphorylation of 4E-BP1, GSK-3/, S6 ribosomal protein have been decreased in melatonin treated animals. In addition, melatonin decreased apoptosis by means of 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 information suggest that Akt phosphorylation, preferably in the Thr308 website on the activation loop through PDK1 and PTEN, mediates melatonin’s neuroprotective activity and improved Akt phosphorylation results in reduced apoptosis.1. Introduction Melatonin is actually a effective cost-free radical scavenger with all the desirable characteristics of a clinically-reliable antioxidant. It detoxifies oxygenand nitrogen-based free radicals and oxidizing agents, which includes the very toxic hydroxyl-and peroxynitrite radicals, initiating lipid peroxidation and neuronal injury [1sirtuininhibitor]. It was previously revealed that melatonin reduced brain injury and DNA damage immediately after ischemic stroke in rodents [4,5]. So far, the neuroprotective impact of melatonin has been linked mostly to its direct free of charge radical scavenging and indirect antioxidant activities [3]. Furthermore, melatonin regulates cellular signaling pathways via receptor-dependent and independent mechanisms [6sirtuininhibitor]. Therefore, it isexpected that the downstream signaling molecules also contribute towards the neuroprotective effects of melatonin. To date, several melatonin LIF Protein Storage & Stability receptors have been characterized in mammalian cells; including Gi protein-coupled metabotropic membrane receptors MT1 (Mel1a), MT2 (Mel1b), and nuclear binding web-sites ROR and RZR [6]. Binding of melatonin to these receptors promotes a number of signaling processes via distinct Gi protein subtypes like Gq/G11, Go, Gz, or G16 [6,8sirtuininhibitor0]. It was reported that activation of Gi protein by melatonin, leads to the phosphorylation of extracellular signal egulated kinases-1/2 (ERK1/2) and c-Jun N-terminal kinases (JNK) through improved activation of phospholipase C (PLC) and protein kinase C (PKC), particularly inside the case of elevated intracellular Ca+2 [6,11,12]. Also, melatonin inhibits cAMP response element-binding protein (CREB) phosphoryla-Correspondence to: Department of Physiology, Istanbul Medipol University, Regenerative and Restorativ.
