Laboratory of Neurodegenerative diseases, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.
Neurotox Res. 2020 Aug;38(2):421-433. doi: 10.1007/s12640-020-00204-1. Epub 2020 May 6.
Excessive alcohol intake affects hippocampal function and neuronal communication through oxidative stress and mitochondrial impairment. Previous studies have suggested that the melanocortin system (MCS) plays an essential role in alcohol consumption and addiction. The MCS is a hypothalamic region involved in regulating inflammatory processes in the brain, and its pharmacological activation through the melanocortin-4 receptor (MC4R) reduces both alcohol consumption and the neuroinflammatory responses in the brain. However, the cellular mechanisms involved in the beneficial actions of MCS against ethanol toxicity are not entirely understood. The objective of this study was to investigate the protective role of the MC4R pharmacological activator RO27-3225 on oxidative damage and mitochondrial impairment present in hippocampal neuronal cultures acutely exposed to ethanol (50, 75 mM, 24 h). Pre-treatment with RO27-3225 (250 nM, 1 h) prevented reactive oxygen species (ROS) increase, dysregulation of cytosolic calcium homeostasis, and mitochondrial potential loss induced by ethanol. Improvement of mitochondrial failure produced by RO27-3225 was accompanied by a significant increase in ATP production in ethanol-treated neurons. More importantly, RO27-3225 promoted the activation of the antioxidant pathway Nrf-2, demonstrated by an increase in the expression and nuclear translocation of Nrf-2, and upregulation of mRNA levels of NAD(P)H quinone oxidoreductase 1 (NQO1), an antioxidant enzyme which expression is activated by this pathway. These results suggest that the stimulation of MC4R prevents oxidative damage and mitochondrial stress induced by ethanol through the activation of the Nrf-2 pathway in cultured hippocampal neurons. These results are novel and demonstrate the critical function of MC4R in promoting antioxidant defense and reducing mitochondrial damage produced by ethanol in the brain.
过量饮酒通过氧化应激和线粒体损伤影响海马功能和神经元通讯。先前的研究表明，黑皮质素系统（MCS）在酒精摄入和成瘾中起着至关重要的作用。MCS 是一个下丘脑区域，参与调节大脑中的炎症过程，其通过黑皮质素-4 受体（MC4R）的药理学激活可减少酒精消耗和大脑中的神经炎症反应。然而，MCS 对抗乙醇毒性的有益作用所涉及的细胞机制尚不完全清楚。本研究的目的是研究 MC4R 药理学激活剂 RO27-3225 对急性暴露于乙醇（50、75mM，24h）的海马神经元培养物中氧化损伤和线粒体损伤的保护作用。RO27-3225（250nM，1h）预处理可防止乙醇引起的活性氧（ROS）增加、细胞溶质钙稳态失调和线粒体电位丧失。RO27-3225 改善线粒体衰竭伴随着乙醇处理神经元中 ATP 产生的显著增加。更重要的是，RO27-3225 促进了抗氧化途径 Nrf-2 的激活，表现为 Nrf-2 的表达和核转位增加，以及 NAD(P)H 醌氧化还原酶 1（NQO1）的 mRNA 水平上调，该途径可激活该酶的表达。这些结果表明，MC4R 的刺激通过激活培养海马神经元中的 Nrf-2 途径，防止了乙醇引起的氧化损伤和线粒体应激。这些结果是新颖的，表明 MC4R 在促进大脑中抗氧化防御和减少乙醇引起的线粒体损伤方面起着关键作用。
