Sesamin protects against neurotoxicity via inhibition of microglial activation under high glucose circumstances through modulating p38 and JNK signaling pathways.

Diabetes mellitus (DM), one of the principal causes of morbidity and mortality worldwide, is implicated in the progression of age-related neurodegenerative diseases (NDDs), in which microglial activation is a crucial mediator. Sesamin, a kind of phytochemical, shows inhibitory effects on microglial activation. The present study studied whether sesamin protects against neurotoxicity triggered by high glucose-induced microglial activation. We firstly demonstrated that high doses of glucose, which mimics hyperglycemia in DM, did induce the activation of murine BV2 microglial cells, increasing inflammatory responses such as the production of ROS or inflammatory mediators like IL-1ß, TNF-⍺, and nitric oxide, through activation of p38 and JNK signaling pathways. Next, conditioned medium (CM) collected from high glucose-activated BV2 cell culture was used to show aggravated neurotoxicity in differentiated PC12 cells, indicating that high glucose-activated microglia could induce neurotoxicity. Interestingly, pretreatment of BV2 cells with sesamin diminished high glucose-induced microglia activation and inflammatory responses. Moreover, neurotoxicity in PC12 cells was found to be decreased in the group treated with CM from the sesamin-pretreated BV2 cell culture, suggesting sesamin inhibited microglial activation, thereby protecting neurons from activated microglia-mediated neurotoxicity. Thus, sesamin might be a potential compound to use in the prevention of diabetic-induced NDDs.

Sesamin Promotes Neurite Outgrowth under Insufficient Nerve Growth Factor Condition in PC12 Cells through ERK1/2 Pathway and SIRT1 Modulation.

The promotion of neurogenesis can be a promising strategy to improve and restore neuronal function in neurodegenerative diseases. Nerve growth factor (NGF) plays a key role in neurite outgrowth and synaptic formation during brain repair stage. Nowadays, there are several studies on the developing methods to enhance the endogenous NGF activity for treatment and restore the neuronal function. In this study, the potentiating effect of sesamin, a major lignan in sesame seeds (Sesamum indicum) and oil, on NGF-induced neurogenesis and its involved mechanisms were firstly reported. Sesamin effectively enhanced the PC12 neuron-like cell differentiation and neurite length under insufficient conditions of NGF. The neuronal markers including synaptophysin and growth-associated protein-43 along with the synaptic connections were significantly increased in combination treatment between sesamin and NGF. Moreover, sesamin also increased the level of phospho-ERK1/2 and SIRT1 protein, an important regulatory protein of the neurogenesis process. The neurogenesis was blocked by the specific SIRT1 inhibitor, JGB1741, suggesting that the neuritogenic effect of sesamin was associated with SIRT1 protein modulation. Taken together, the potentiating effect of sesamin on NGF-induced neurogenesis in this finding could be used for alternative treatment in neurodegenerative diseases, including Alzheimer's disease.

Protocatechuic acid inhibits inflammatory responses in LPS-activated BV2 microglia via regulating SIRT1/NF-κB pathway contributed to the suppression of microglial activation-induced PC12 cell apoptosis.

SIRT1 exhibits inhibitory effects on microglial activation-induced neurodegeneration. Regulating SIRT1 may become a novel approach for curing neurodegenerative diseases. Protocatechuic acid (PA), a phenolic acid, has anti-neuroinflammatory effects. The effect of PA on SIRT1 in activated microglia remains unknown. Here, we examined whether PA has anti-inflammatory effects against microglial activation-induced neuronal cell death via regulating SIRT1 in microglia. We found that PA inhibited the release of inflammatory mediators in LPS-activated BV2 microglia via the SIRT1/NF-κB pathway and thereby attenuated microglial activation-induced PC12 cell apoptosis. This suggests that SIRT1 mediates the anti-neuroinflammatory effects of PA to ameliorate microglial activation-induced neuron death.

Cyanidin-3-O-Glucoside Protects PC12 Cells Against Neuronal Apoptosis Mediated by LPS-Stimulated BV2 Microglial Activation.

Neuroinflammation is a major factor in the pathogenesis of various neurodegenerative diseases. Microglia are resident macrophages that act as key mediators of inflammation in the brain. In response to inflammatory stimuli including lipopolysaccharide (LPS), microglial activation occurs immediately. Overproduction of inflammatory mediators released by activated microglia contributes to neuron damage in neurodegenerative disease. Therefore, identification of a compound that has anti-inflammatory activities and inhibits microglial activation may be an alternative therapeutic approach for the treatment of neurodegenerative diseases. Cyanidin-3-O-glucoside (C3G), a type of anthocyanin, possesses powerful anti-inflammatory activities. In this study, the anti-inflammatory effects of C3G were investigated in LPS-stimulated BV2 microglia. The results indicate that pretreatment with C3G significantly suppresses microglial activation and the production of neurotoxic mediators including nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in LPS-activated BV2 cells. Moreover, C3G downregulates the gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines via the suppression of NF-κB and p38 MAPK signaling pathways. Furthermore, a co-culture system to determine the indirect neuroprotective effects of C3G was used. Results demonstrated that conditioned medium (CM) from LPS-stimulated BV2 cells can promote the apoptosis of differentiated pheochromocytoma (PC12) cells through the activation of caspase-3, while C3G pretreatment in BV2 microglia can protect differentiated PC12 cells from microglial activation-induced apoptosis. Therefore, C3G may be a potential therapeutic agent for the treatment and prevention of neurodegenerative diseases associated with microglial activation.