Melatonin Protective Effect Against Amyloid Β-Induced Neurotoxicity Mediated by Mitochondrial Biogenesis; Involvement of Hippocampal Sirtuin-1 Signaling Pathway Publisher Pubmed



Ansari Dezfouli M¹ ; Zahmatkesh M^{1, 2} ; Farahmandfar M¹ ; Khodagholi F³ Show Affiliations
Source: Physiology and Behavior Published:2019

Abstract

Melatonin has a potential therapeutic value in Alzheimer's disease (AD), a disease that is associated with a dramatic decline in memory and cognitive abilities. The aggregation of the amyloid β (Aβ) peptide, a hallmark of AD, deactivates mitochondrial biogenesis and antioxidant defenses. Melatonin as an endogenous antioxidant, decreases in plasma and cerebrospinal fluid of AD patients. Even though several experimental studies have demonstrated the melatonin neuroprotection in AD, clinical trials of melatonin therapy have not yet confirmed outstanding results in AD patients. Better understanding of the molecular mechanisms involved in melatonin neuroprotective effects may pave the way for an efficient therapy. Hence, we investigated the involvement of silent information regulator 1 (SIRT1) signaling and mitochondrial biogenesis in melatonin neuroprotection in a rat model of cognitive impairment induced by intra-hippocampal Aβ injection. Animals assigned to melatonin treatment in the presence or absence of SIRT1 inhibitor (EX527), for 14 consecutive days. Spatial working memory and anxiety level were examined with Y-maze and elevated plus maze tests respectively. Hippocampal SIRT1, transcription factor-A mitochondrial (TFAM) and mitochondrial DNA (mtDNA) copy number were measured. We observed a decrease in hippocampal SIRT1, which accompanied with reduction in TFAM and mtDNA copy number in the Aβ-injected rats. Melatonin treatment increased hippocampal SIRT1 and TFAM expression and enhanced mtDNA copy number in the hippocampus. It also improved memory, ameliorated the anxiety, and attenuated hippocampal cell damage in the Aβ-injected animals. These effects were blocked by EX527 administration, suggesting SIRT1 signaling involvement in melatonin neuroprotective effect. This mechanism may introduce a new promising strategy in battle against AD. © 2019 Elsevier Inc.