Major depressive disorder (MDD) is a life‐threatening illness characterized by mood changes and high rates of suicide. Although the role of neuroinflammation in MMD has been studied, the mechanistic interplay between antidepressants, neuroinflammation, and autophagy is yet to be investigated. The present study investigated the effect of melatonin on LPS‐induced neuroinflammation, depression, and autophagy impairment. Our results showed that in mice, lipopolysaccharide (LPS) treatment induced depressive‐like behaviors and caused autophagy impairment by dysregulating ATG genes. Moreover, LPS treatment significantly increased the levels of cytokines (TNFα, IL‐1β, IL‐6), enhanced NF‐ᴋB phosphorylation, caused glial (astrocytes and microglia) cell activation, dysregulated FOXO3a expression, increased the levels of redox signaling molecules such as ROS/TBARs, and altered expression of Nrf2, SOD2, and HO‐1. Melatonin treatment significantly abolished the effects of LPS, as demonstrated by improved depressive‐like behaviors, normalized autophagy‐related gene expression, and reduced levels of cytokines. Further, we investigated the role of autophagy in LPS‐induced depressive‐like behavior and neuroinflammation using autophagy inhibitors 3‐MA and Ly294002. Interestingly, inhibitor treatment significantly abolished and reversed the anti‐depressive, pro‐autophagy, and anti‐inflammatory effects of melatonin. The present study concludes that the anti‐depressive effects of melatonin in LPS‐induced depression might be mediated via autophagy modulation through FOXO3a signaling.
Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, starting from acute ATP loss and ionic imbalance to subsequent membrane depolarization, glutamate excitotoxicity, and calcium overload. These initial events are followed by neuroinflammation and oxidative stress, eventually causing neuronal neurosis and apoptosis. Complicated interplays exist between these steps happening across various stages, which not only represent the complicated nature of ischemic pathology but also warrant a detailed delineation of the underlying molecular mechanisms to develop better therapeutic options. In the present study, we examined the neuroprotective effects of polydatin against ischemic brain injury using a rat model of permanent middle cerebral artery occlusion (MCAO). Our results demonstrated that polydatin treatment reduced the infarction volume and mitigated the neurobehavioral deficits, sequentially rescued neuronal apoptosis. Ischemic stroke induced an elevation of neuroinflammation and reactive oxygen species, which could be attenuated by polydatin via the reduced activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In addition, polydatin upregulated the endogenous antioxidant nuclear factor erythroid 2-related factor 2, heme oxygenase-1, the thioredoxin pathway, and eventually reversed ischemic-stroke-induced elevation of ROS and inflammation in ischemic cortical tissue. The diverse and broad actions of polydatin suggested that it could be a multiple targeting neuroprotective agent in ameliorating the detrimental effects of MCAO, such as neuroinflammation, oxidative stress, and neuronal apoptosis. As repetitive clinical trials of neuroprotectants targeting a single step of stroke pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles in MCAO.
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