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Chronic manganese (Mn) exposure can disturb mitochondrial homeostasis leading to mitochondrial dysfunction, which is involved in Mn‐induced neurodegenerative diseases. Resveratrol (RSV), as a promoter of mitochondrial biogenesis, plays a significant role against mitochondrial dysfunction. However, whether RSV can relieve Mn‐induced neuronal injury and mitochondrial dysfunction remains unknown. Sirtuin 3 (SIRT3), a main mitochondrial sirtuin, is an important regulator of mitochondria to maintain mitochondrial homeostasis. Therefore, this study investigated whether SIRT3 was required for RSV alleviating Mn‐induced mitochondrial dysfunction in primary cultured neurons from C57BL/6 mice. Here, we showed that Mn (100 and 200 μM) exposure for 24 hr caused significant neuronal damage and mitochondrial dysfunction through increasing mitochondrial ROS, reducing mitochondrial membrane potential and adenosine triphosphate level, and leading to mitochondrial network fragmentation, which could be ameliorated by RSV pretreatment in primary cultured neurons. Additionally, our results also indicated that RSV could activate the SIRT1/PGC‐1α signaling pathway and alleviate Mn‐induced disruption of mitochondrial biogenesis by increasing SIRT1 expression and activity, enhancing deacetylation of PGC‐1α. Furthermore, SIRT3 over‐expression increased deacetylation of mitochondrial transcription factor A and mitochondrial DNA (mtDNA) copy number. Oppositely, silencing SIRT3 increased acetylation of mitochondrial transcription factor A and decreased mtDNA copy number. Our results showed SIRT3 was required for the protective effect of RSV in mitochondrial biogenesis. In conclusion, our findings demonstrated that RSV could ameliorate Mn‐induced neuronal injury and mitochondrial dysfunction in primary cultured neurons through activating the SIRT1/ PGC‐1α signaling pathway, and that SIRT3 is required for promoting mitochondrial biogenesis and attenuating Mn‐induced mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Overexposure to manganese (Mn) is an important environmental risk factor for Parkinsonian-like symptoms referred to as manganism. Alpha-synuclein (α-Syn) oligomerization is a major cause in Mn-induced neurotoxicity. Autophagy, as an adjust response to control intracellular protein homeostasis, is involved in the degradation of α-Syn monomers or oligomers. Furthermore, autophagy dysregulation is also related to development of neurodegenerative disorders. Hence, we speculated that there was an interaction effect between α-Syn oligomerization and autophagy upon Mn exposure. In this study, we applied α-Syn gene knockout mice (α-Syn−/−) and wild-type mice (α-Syn+/+) treated with three different concentrations of MnCl2 (50, 100, and 200 μmol/kg) to elucidate the physiological role of α-Syn in Mn-induced autophagy dysregulation and neurocytes injury. We found that activation of chaperone-mediated autophagy (CMA) pathway by Mn was independent of α-Syn. Additionally, α-Syn could ameliorate excessive autophagy induced by high dose Mn (200 μmol/kg). Next, we used 5 mg/kg Rapamycin (Rap) or 3-methyladenine (3-MA) to regulate autophagy. The study revealed that autophagy is involved in Mn-induced α-Syn oligomerization and neurocytes injury. Taken together, these findings indicated that α-Syn oligomerization might be the major responsible for the Mn-induced autophagy dysregulation and neurocytes injury. [ABSTRACT FROM AUTHOR]

ABSTRACT Overexposure to manganese (Mn) has been known to disrupt neurotransmitter release in the brain. However, the underlying mechanisms of Mn exposure on neurotransmitter vesicle release are still unclear. The current study investigated whether the protein expression and their interaction of SNARE complex associated proteins were the media between Mn exposure and neurotransmitter vesicle fusion disorders. After the neurons were respectively exposed to Mn (0-200 μM) for 0, 6, 12, 18, 24 h, there were different degrees of cell injury in neurons. According to the results, Mn exposures in subsequent experiments were restricted to concentrations of 100 μM for 0, 6, 12, 18, 24 h. Mn was found to down-regulate the expression of SNAP-25 and up-regulate the expression of VAMP-2 in cultured neurons. Moreover, the interaction of Munc 18 and Syntaxin increased significantly in response to Mn treatment for 18-24h, and the interaction of VAMP-2 and Synaptophysin increased first and then decreased. FM1-43-labeled synaptic vesicles also provided evidence that the treatment with Mn resulted in neurotransmitter vesicle fusion increasing first and then decreasing, which was consistent with the 80 kDa protein levels of SNARE complexes. The findings clearly demonstrated that Mn induced the disorders of neurotransmitter vesicle release via disturbing the protein expression and their interaction of SNARE complex associated proteins. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 705-716, 2017. [ABSTRACT FROM AUTHOR]

Exposure to benzo(a)pyrene (BaP) has been shown to cause mitochondrial dysfunction and injury to neural cells. Resveratrol (RSV) has been studied as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent and can modulate mitochondrial function in vitro and in vivo. However, the molecular mechanisms underlying RSV's protection against mitochondrial dysfunction have not been fully elucidated. To investigate whether RSV can effectively prevent BaP-induced mitochondrial dysfunction, we tested the effects of RSV in primary neuronal models. Our results confirmed that neurons exhibited mitochondrial dysfunction and apoptosis in the mitochondrial pathway after BaP-treatment, and that pretreatment with RSV could reduce that dysfunction. Further, our results indicated that RSV pretreatment enhanced mitochondrial biogenesis via the AMPK/PGC-1α pathway and activated mitophagy via the PINK1-Parkin and AMPK/ULK1 pathways, thereby coordinating mitochondrial homeostasis. We also found that RSV could alleviate mitochondrial network fragmentation caused by BaP. This work provided insights into the role of RSV in preventing BaP-induced primary neuronal apoptosis in the mitochondrial pathway, mainly via regulation of mitochondrial biogenesis and mitophagy through AMPK pathway, thus maintaining the integrity of the mitochondrial network. Image 1 • BaP can induce neuronal damage in mitochondrial apoptotic pathways. • RSV can relieve BaP-induced disruption of mitochondrial homeostasis. • RSV enhances mitochondrial biogenesis by AMPK/PGC-1α signaling pathway. • RSV regulates mitophagy via AMPK/ULK1 signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Methylmercury (MeHg) is one of the ubiquitous environmental toxicants, which can induce oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, little is known of the interaction between oxidative stress and Glu metabolism play in MeHg poisoning rats. We have investigated the neuroprotective role of MK-801, a non-competitive N-methyl-d-aspartate receptors (NMDAR) antagonist, against MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK-801 control group, MeHg-treated group (4 and 12μmol/kg) and MK-801 pre-treated group. Administration of MeHg at a dose of 12μmol/kg for four weeks significantly increased in ROS and total Hg levels and that caused lipid, protein and DNA peroxidative damage in cerebral cortex. In addition, MeHg also reduced nonenzymic (reduced glutathione, GSH) and enzymic (glutathione peroxidase, GPx and superoxide dismutase, SOD) antioxidants and enhanced neurocyte apoptosis rate in cerebral cortex. MeHg-induced ROS production appears to inhibit the activity of the glutamine synthetase (GS), leading to Glu metabolism dysfunction. Pretreatment with MK-801 at a dose of 0.3μmol/kg prevented the alterations of the activities of PAG and GS and oxidative stress. In addition, pretreatment with MK-801 significantly alleviated the neurocyte apoptosis rate and histopathological damage. In conclusion, the results suggested ROS formation resulting from MeHg- and Glu-induced oxidative stress contributed to neuronal injury. MK-801 possesses the ability to attenuate MeHg-induced neurotoxicity in the cerebral cortex through mechanisms involving its NMDA receptor binding properties and antioxidation. [Copyright &y& Elsevier]

Highlights: [•] Mn could cause nerve cell damage in a time-dependent manner. [•] ER stress signaling was involved in Mn-induced neurotoxicity. [•] Mn induced the ER stress via activation of PERK and IRE1 signaling pathways. [ABSTRACT FROM AUTHOR]

• The exposure of BaP could cause neurobehavioral deficits in rats. • BaP induced nerve cells damage in hippocampus. • BaP induced disruption of mitochondrial biogenesis and mitophagy in hippocampus. • RSV could ameliorate BaP-induced the cell apoptosis and mitochondrial damage. • The protective effect of RSV was associated with activating AMPK/PGC-1α signals. Exposure to benzo(a)pyrene (BaP) is associated with poor neurodevelopment in children and memory impairment in adults. Previous research has demonstrated that mitochondrial damage plays an important role in BaP-induced neurotoxicity. Of interest, increasing evidence has suggested that resveratrol (RSV) can alleviate nerve cell damage, however the exact mechanisms of biological activity in mitochondria are not fully understood. In the current study, Wistar rats were exposed to BaP (1, 2, 4 mg/kg) and/or RSV (15, 30 mg/kg) during embryonic development and adolescence, and learning and memory ability, mitochondrial damage, and the expression of proteins associated with mitochondrial biogenesis and mitophagy were evaluated. These studies indicated that 2 and 4 mg/kg BaP could induce disorders of mitochondrial biogenesis and mitophagy, which leads to abnormal nerve cell development. However, pretreatment with 30 mg/kg RSV alleviated cell damage and the disorder of mitochondrial biogenesis by activating the AMPK/PGC-1α signaling pathway and promoting mitophagy. These findings suggested that RSV had utility in promoting mitochondrial homeostasis against BaP-induced nerve cell damage in the hippocampus of rats. [ABSTRACT FROM AUTHOR]