Activation of the Melanocortin-4 Receptor Prevents Oxidative Damage and Mitochondrial Dysfunction in Cultured Hippocampal Neurons Exposed to Ethanol

Autor:	Carola Tapia-Monsalves, María José Pérez, Alejandra Aranguiz, Rodrigo A. Quintanilla, Gloria Mendez
Rok vydání:	2020
Předmět:	0301 basic medicine NF-E2-Related Factor 2 Hippocampal formation Mitochondrion Toxicology medicine.disease_cause Hippocampus Antioxidants 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine NAD(P)H Dehydrogenase (Quinone) Animals RNA Messenger Cells Cultured chemistry.chemical_classification Inflammation Membrane Potential Mitochondrial Neurons Reactive oxygen species Ethanol Chemistry General Neuroscience Central Nervous System Depressants Cell biology Mitochondria Rats Melanocortin 4 receptor Oxidative Stress 030104 developmental biology Neuroprotective Agents Receptor Melanocortin Type 4 Calcium NAD+ kinase Melanocortin Peptides Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress
Zdroj:	Neurotoxicity research. 38(2)
ISSN:	1476-3524
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::349d3e91d3a74769831285047d4e122c https://pubmed.ncbi.nlm.nih.gov/32378055 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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