Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats
Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats
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DOI：
10.1111/j.1460-9568.2006.05298.x
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发表时间：
2007-01-01
影响因子：
3.4
通讯作者：
Guerri, Consuelo
中科院分区：
文献类型：
--
作者：
Pascual, Maria;Blanco, Ana M.;Guerri, Consuelo
青少年的大脑发育似乎对大脑结构和行为的成熟很重要。间歇性酗酒在青少年中很常见，这种类型的饮酒会导致脑损伤。因为我们已经证明，慢性乙醇治疗诱导炎症过程中的大脑，我们调查是否间歇性乙醇中毒增强环氧合酶-2（考克斯-2）和诱导型一氧化氮合酶（iNOS）在青春期大鼠，以及这些介质是否诱导脑损伤，并导致永久性认知功能障碍。青春期大鼠暴露于乙醇（3.0克/公斤）连续两天，在48小时的间隔超过14天。在最后一次乙醇给药后24 h，在新皮质、海马和小脑中评估考克斯-2、NOS和细胞死亡的水平。第二天或末次注射后20天（成年期），对动物进行不同的行为测试（条件性辨别学习、旋转棒、物体识别、横梁行走性能），以评估认知和运动功能。我们的研究结果表明，间歇性酒精中毒上调考克斯-2和iNOS的水平，并增加新皮层，海马和小脑的细胞死亡。此外，在青春期用乙醇处理的动物表现出行为缺陷，这在乙醇处理结束时和成年阶段是明显的。给予吲哚美辛（一种考克斯-2抑制剂）可消除对考克斯-2和iNOS表达的诱导以及细胞死亡，从而预防乙醇诱导的行为缺陷。这些研究结果表明，在青春期酗酒暴露于乙醇会通过炎症过程引起脑损伤，并导致长期的神经行为后果。因此，施用吲哚美辛保护免受乙醇诱导的脑损伤，并防止乙醇对认知和运动过程的有害影响。
Adolescent brain development seems to be important for the maturation of brain structures and behaviour. Intermittent binge ethanol drinking is common among adolescents, and this type of drinking can induce brain damage. Because we have demonstrated that chronic ethanol treatment induces inflammatory processes in the brain, we investigate whether intermittent ethanol intoxication enhances cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in adolescent rats, and whether these mediators induce brain damage and cause permanent cognitive dysfunctions. Adolescent rats were exposed to ethanol (3.0 g/kg) for two consecutive days at 48-h intervals over 14 days. Levels of COX-2, NOS and cell death were assessed in the neocortex, hippocampus and cerebellum 24 h after the final ethanol administration. The following day or 20 days after the final injection (adult stage), animals were tested for different behavioural tests (conditional discrimination learning, rotarod, object recognition, beam-walking performance) to assess cognitive and motor functions. Our results show that intermittent ethanol intoxication upregulates COX-2 and iNOS levels, and increases cell death in the neocortex, hippocampus and cerebellum. Furthermore, animals treated with ethanol during adolescence exhibited behavioural deficits that were evident at the end of ethanol treatments and at the adult stage. Administration of indomethacin, a COX-2 inhibitor, abolishes the induction of COX-2 and iNOS expression and cell death, preventing ethanol-induced behavioural deficits. These findings indicate that binge pattern exposure to ethanol during adolescence induces brain damage by inflammatory processes and causes long-lasting neurobehavioural consequences. Accordingly, administering indomethacin protects against ethanol-induced brain damage and prevents detrimental ethanol effects on cognitive and motor processes.