RESUMEN
Arsenic contamination of groundwater remains a serious public health problem worldwide. Arsenic-induced neurotoxicity receives increasing attention, however, the mechanism remains unclear. Hippocampal neuronal death is regarded as the main event of arsenic-induced cognitive dysfunction. Mitochondria lesion is closely related to cell death, however, the effects of arsenic on PGAM5-regulated mitochondrial dynamics has not been documented. Crosstalk between autophagy and apoptosis is complicated and autophagy has a dual role in the apoptosis pathways in neuronal cells. In this study, arsenic exposure resulted in mitochondrial PGAM5 activation and subsequent activation of apoptosis and AMPK-mTOR dependent autophagy. Intervention by autophagy activator Rapamycin or inhibitor 3-MA, both targeting at mTOR, accordingly induced activation or inhibition of apoptosis. Intervention by MK-3903 or dorsomorphin, activator or inhibitor of AMPK, received similar results. Our findings suggested that arsenic-induced PGAM5 activation played a role in AMPK-mTOR dependent autophagy and arsenic induced autophagy-dependent apoptosis in hippocampal neurons via AMPK/mTOR signaling pathway.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Arsénico , Proteínas Quinasas Activadas por AMP/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Apoptosis , Autofagia , Neuronas , HipocampoRESUMEN
Arsenic pollution in groundwater remains a serious public health concern around the world. Recent years, arsenic-related neurological and psychiatric disorders have been reported increasingly. However, the exact mechanisms of it remains elusive. In this study, arsenic exposure through drinking water resulted in depression-/anxiety-like behaviors in mice accompanied by oxidative stress and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation in prefrontal cortex (PFC) and hippocampus, two main affected areas found in neurobehavioral disorders. Intervention by NAC, a ROS scavenger, diminished the social behavior impairments in mice as well as ROS generation and NLRP3 inflammasome activation. Further study revealed that it was p38 MAPK signaling pathway that mediated ROS-induced NLRP3 inflammasome activation. Overall, our findings suggested that ROS/p38 MAPK/NLRP3 inflammasome cascade was involved in arsenic-induced depression-/anxiety-disorders. Furthermore, NAC might be a potential therapeutic agent for arsenic-induced depression-/anxiety-disorders by inhibiting both ROS generation and ROS-induced NLRP3 inflammasome activation.