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.
Baicalein, one of the major flavonoids found in Scutellaria baicalensis Georgi, displays neuroprotective effects on experimental models of Parkinson's disease (PD) in vitro and in vivo. Although the antioxidative and/or anti-inflammatory activity of baicalein likely contributes to these neuroprotective effects, other modes of action remain largely uncharacterized. In the present study, baicalein pretreatment significantly prevented cells from 6-hydroxydopamine (6-OHDA)-induced damage by attenuating cellular apoptosis. However, post-treatment with baicalein did not show any restorative effect against 6-OHDA-induced cellular damage. We found that baicalein increased transcriptional factor NF-E2-related factor 2 (Nrf2)/hemo oxygenase 1(HO-1) protein expression and decreased Kelch-like ECH-associated protein 1 (Keap1) in a time- and concentration-dependent manner in PC12 cells. In addition, baicalein induced Nrf2 nuclear translocation and enhanced antioxidant response element (ARE) transcriptional activity, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, we demonstrated that cytoprotective effects of baicalein could be attenuated by Nrf2 siRNA transfection and the HO-1 inhibitor zinc protoporphyrin (Znpp) as well as the proteasome inhibitor MG132. Furthermore, PKCα and AKT protein phosphorylation were up-regulated by baicalein pretreatment, and selective inhibitors targeted to PKC, PI3K, and AKT could block the cytoprotective effects of baicalein. Taken together, our results indicate that baicalein prevented PC12 cells from 6-OHDA-induced oxidative damage via the activation of Keap1/Nrf2/HO-1, and it also involves the PKCα and PI3K/AKT signaling pathway. Ultimately, the neuroprotective effects of baicalein may endue baicalein as a promising candidate for the prevention of PD.
BackgroundWhile all anti-diabetic agents can decrease blood glucose level directly or indirectly, few are able to protect and preserve both pancreatic beta cell mass and their insulin-secreting functions. Thus, there is an urgent need to find an agent or combination of agents that can lower blood glucose and preserve pancreatic beta cells at the same time. Herein, we report a dual-functional andrographolide-lipoic acid conjugate (AL-1). The anti-diabetic and beta cell protective activities of this novel andrographolide-lipoic acid conjugate were investigated.MethodsIn alloxan-treated mice (a model of type 1 diabetes), drugs were administered orally once daily for 6 days post-alloxan treatment. Fasting blood glucose and serum insulin were determined. Pathologic and immunohistochemical analysis of pancreatic islets were performed. Translocation of glucose transporter subtype 4 in soleus muscle was detected by western blot. In RIN-m cells in vitro, the effect of AL-1 on H2O2-induced damage and reactive oxidative species production stimulated by high glucose and glibenclamide were measured. Inhibition of nuclear factor kappa B (NF-κB) activation induced by IL-1β and IFN-γ was investigated.ResultsIn alloxan-induced diabetic mouse model, AL-1 lowered blood glucose, increased insulin and prevented loss of beta cells and their dysfunction, stimulated glucose transport protein subtype 4 (GLUT4) membrane translocation in soleus muscles. Pretreatment of RIN-m cells with AL-1 prevented H2O2-induced cellular damage, quenched glucose and glibenclamide-stimulated reactive oxidative species production, and inhibited cytokine-stimulated NF-κB activation.ConclusionWe have demonstrated that AL-1 had both hypoglycemic and beta cell protective effects which translated into antioxidant and NF-κB inhibitory activity. AL-1 is a potential new anti-diabetic agent.
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