背景:酒精,一种被广泛滥用的药物,显著降低生活质量,导致慢性疾病和精神病,严重的健康,社会,和经济影响。以前,我们证明,非自愿饮酒可增加青春期大鼠星形胶质细胞Cx43半通道和Panx1通道的开放.然而,乙醇是否直接影响星形胶质半通道,如果是,这如何影响星形胶质细胞的功能和存活仍有待阐明。
结果:临床相关浓度的乙醇促进小鼠皮质星形胶质细胞中Cx43半通道和Panx1通道的开放,导致ATP和谷氨酸的释放。这些大孔通道的激活依赖于Toll样受体4,P2X7受体,IL-1β和TNF-α信号,p38丝裂原活化蛋白激酶,和诱导型一氧化氮(NO)合酶。值得注意的是,乙醇诱导的Cx43半通道和Panx1通道的开放导致细胞因子分泌的改变,不生产,胶质发射器释放,和星形胶质细胞反应性,最终影响生存。
结论:我们的研究揭示了乙醇损害星形胶质细胞功能的新机制,涉及炎症途径的顺序刺激,进一步增加Cx43半通道和Panx1通道的开放。我们假设,在各种酒精使用障碍的进展过程中,靶向星形胶质细胞半通道可能是一种有前途的药理学方法,可以保持星形胶质细胞功能和突触可塑性。
BACKGROUND: Alcohol, a widely abused drug, significantly diminishes life quality, causing chronic diseases and psychiatric issues, with severe health, societal, and economic repercussions. Previously, we demonstrated that non-voluntary alcohol consumption increases the opening of Cx43
hemichannels and Panx1 channels in astrocytes from adolescent rats. However, whether ethanol directly affects astroglial
hemichannels and, if so, how this impacts the function and survival of astrocytes remains to be elucidated.
RESULTS: Clinically relevant concentrations of ethanol boost the opening of Cx43
hemichannels and Panx1 channels in mouse cortical astrocytes, resulting in the release of ATP and glutamate. The activation of these large-pore channels is dependent on Toll-like receptor 4, P2X7 receptors, IL-1β and TNF-α signaling, p38 mitogen-activated protein kinase, and inducible nitric oxide (NO) synthase. Notably, the ethanol-induced opening of Cx43
hemichannels and Panx1 channels leads to alterations in cytokine secretion, NO production, gliotransmitter release, and astrocyte reactivity, ultimately impacting survival.
CONCLUSIONS: Our study reveals a new mechanism by which ethanol impairs astrocyte function, involving the sequential stimulation of inflammatory pathways that further increase the opening of Cx43 hemichannels and Panx1 channels. We hypothesize that targeting astroglial
hemichannels could be a promising pharmacological approach to preserve astrocyte function and synaptic plasticity during the progression of various alcohol use disorders.