Ibáñez Cristina, Acuña Tirso, Quintanilla María Elena, Pérez-Reytor Diliana, Morales Paola, Karahanian Eduardo
Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago 8910060, Chile.
Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders, Santiago 8910060, Chile.
Antioxidants (Basel). 2023 Sep 13;12(9):1758. doi: 10.3390/antiox12091758.
High ethanol consumption triggers neuroinflammation, implicated in sustaining chronic alcohol use. This inflammation boosts glutamate, prompting dopamine release in reward centers, driving prolonged drinking and relapse. Fibrate drugs, activating peroxisome proliferator-activated receptor alpha (PPAR-α), counteract neuroinflammation in other contexts, prompting investigation into their impact on ethanol-induced inflammation. Here, we studied, in UChB drinker rats, whether the administration of fenofibrate in the withdrawal stage after chronic ethanol consumption reduces voluntary intake when alcohol is offered again to the animals (relapse-type drinking). Furthermore, we determined if fenofibrate was able to decrease ethanol-induced neuroinflammation and oxidative stress in the brain. Animals treated with fenofibrate decreased alcohol consumption by 80% during post-abstinence relapse. Furthermore, fenofibrate decreased the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukins IL-1β and IL-6, and of an oxidative stress-induced gene (heme oxygenase-1), in the hippocampus, nucleus accumbens, and prefrontal cortex. Animals treated with fenofibrate showed an increase M2-type microglia (with anti-inflammatory proprieties) and a decrease in phagocytic microglia in the hippocampus. A PPAR-α antagonist (GW6471) abrogated the effects of fenofibrate, indicating that they are dependent on PPAR-α activation. These findings highlight the potential of fenofibrate, an FDA-approved dyslipidemia medication, as a supplementary approach to alleviating relapse severity in individuals with alcohol use disorder (AUD) during withdrawal.
高乙醇摄入量会引发神经炎症，这与持续的慢性酒精使用有关。这种炎症会增加谷氨酸，促使奖励中枢释放多巴胺，从而导致长期饮酒和复饮。贝特类药物可激活过氧化物酶体增殖物激活受体α（PPAR-α），在其他情况下可对抗神经炎症，因此促使人们研究其对乙醇诱导的炎症的影响。在此，我们研究了在UChB饮酒大鼠中，在慢性乙醇摄入后的戒断阶段给予非诺贝特是否会降低再次给动物提供酒精时的自愿摄入量（复饮型饮酒）。此外，我们还确定了非诺贝特是否能够降低乙醇诱导的大脑神经炎症和氧化应激。用非诺贝特治疗的动物在戒酒期复饮期间酒精摄入量减少了80%。此外，非诺贝特降低了海马体、伏隔核和前额叶皮质中促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素IL-1β和IL-6以及氧化应激诱导基因（血红素加氧酶-1）的表达。用非诺贝特治疗的动物海马体中M2型小胶质细胞（具有抗炎特性）增加，吞噬性小胶质细胞减少。PPAR-α拮抗剂（GW6471）消除了非诺贝特的作用，表明这些作用依赖于PPAR-α的激活。这些发现凸显了非诺贝特（一种经美国食品药品监督管理局批准用于治疗血脂异常的药物）作为一种辅助方法来减轻酒精使用障碍（AUD）患者戒断期间复饮严重程度的潜力。
