Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.

Background: An imbalance of free radicals and antioxidant defense systems in physiological processes can result in protein/DNA damage, inflammation, and cellular apoptosis leading to neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Sesamin and sesamol, compounds derived from sesame seeds and oil, have been reported to exert various pharmacological effects, especially antioxidant activity. However, their molecular mechanisms against the oxidative stress induced by exogenous hydrogen peroxide (H₂O₂) remain to be elucidated. Aim: In this study, neuroprotective effects of sesamin and sesamol on H₂O₂-induced human neuroblastoma (SH-SY5Y) cell death and possible signaling pathways in the cells were explored. Methods: MTT assay and flow cytometry were conducted to determine cell viability and apoptotic profiles of neuronal cells treated with sesamin and sesamol. Carboxy-DCFDA assay was used to measure reactive oxygen species (ROS). Moreover, Western blot analysis was performed to investigate protein profiles associated with neuroprotection. Results: Pretreatment of the cells with 1 µM of sesamin and sesamol remarkably reduced the SH-SY5Y cell death induced by 400 µM H₂O₂ as well as the intracellular ROS production. Moreover, the molecular mechanisms underlying neuroprotection of the compounds were associated with activating SIRT1-SIRT3-FOXO3a expression, inhibiting BAX (proapoptotic protein), and upregulating BCL-2 (anti-apoptotic protein). Conclusion: The findings suggest that sesamin and sesamol are compounds that potentially protect neuronal cells against oxidative stress similar to that of the resveratrol, the reference compound. These antioxidants are thus of interest for further investigation in in vivo models of neuroprotection.

Viral infections of the central nervous system (CNS) cause variable outcomes from acute to severe neurological sequelae with increased morbidity and mortality. Viral neuroinvasion directly or indirectly induces encephalitis via dysregulation of the immune response and contributes to the alteration of neuronal function and the degeneration of neuronal cells. This review provides an overview of the cellular and molecular mechanisms of virus-induced neurodegeneration. Neurotropic viral infections influence many aspects of neuronal dysfunction, including promoting chronic inflammation, inducing cellular oxidative stress, impairing mitophagy, encountering mitochondrial dynamics, enhancing metabolic rewiring, altering neurotransmitter systems, and inducing misfolded and aggregated pathological proteins associated with neurodegenerative diseases. These pathogenetic mechanisms create a multidimensional injury of the brain that leads to specific neuronal and brain dysfunction. The understanding of the molecular mechanisms underlying the neurophathogenesis associated with neurodegeneration of viral infection may emphasize the strategies for prevention, protection, and treatment of virus infection of the CNS.

Neuronal cells exposed to H₂O₂may undergo increase ROS, reduction in cell viability and cell death. Butein, isoliquiritigenin, and scopoletin ameliorated H₂O₂-induced neurotoxicity by reducing ROS, balancing antioxidants and activating SIRT1-FoxO3a-ADAM10 pathway.

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, causes high mortality rates in humans and it is the most clinically important and common cause of viral encephalitis in Asia. To date, there is no specific treatment for JEV infection. Melatonin, a neurotropic hormone, is reported to be effective in combating various bacterial and viral infections. However, the effects of melatonin on JEV infection have not yet been studied. The investigation tested the antiviral effects of melatonin against JEV infection and elucidated the possible molecular mechanisms of inhibition. Melatonin inhibited the viral production in JEV-infected SH-SY5Y cells in a time- and dose-dependent manner. Time-of-addition assays demonstrated a potent inhibitory effect of melatonin at the post-entry stage of viral replication. Molecular docking analysis revealed that melatonin negatively affected viral replication by interfering with physiological function and/or enzymatic activity of both JEV nonstructural 3 (NS3) and NS5 protein, suggesting a possible underlying mechanism of JEV replication inhibition. Moreover, treatment with melatonin reduced neuronal apoptosis and inhibited neuroinflammation induced by JEV infection. The present findings reveal a new property of melatonin as a potential molecule for the further development of anti-JEV agents and treatment of JEV infection.