Programa de Pós-Graduação em Medicina e Ciências da Saúde, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratório de Neuroquímica e Psicofarmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil; Instituto Nacional de Ciência e Tecnologia em Doenças Cerebrais, Excitotoxicidade e Neuroproteção, Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratório de Neuroquímica e Psicofarmacologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil; Instituto Nacional de Ciência e Tecnologia em Doenças Cerebrais, Excitotoxicidade e Neuroproteção, Porto Alegre, RS, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2022 Dec 20;119:110602. doi: 10.1016/j.pnpbp.2022.110602. Epub 2022 Jul 16.
Huntington's disease (HD) is a neurodegenerative disorder, characterized by motor dysfunction, psychiatric disturbance, and cognitive decline. In the early stage of HD, occurs a decrease in dopamine D receptors and adenosine A receptors (AR), while in the late stage also occurs a decrease in dopamine D receptors and adenosine A receptors (AR). Adenosine exhibits neuromodulatory and neuroprotective effects in the brain and is involved in motor control and memory function. 3-Nitropropionic acid (3-NPA), a toxin derived from plants and fungi, may reproduce HD behavioral phenotypes and biochemical characteristics. This study investigated the effects of acute exposure to CPA (AR agonist), CGS 21680 (AR agonist), caffeine (non-selective of AR and AR antagonist), ZM 241385 (AR antagonist), DPCPX (AR antagonist), dipyridamole (inhibitor of nucleoside transporters) and EHNA (inhibitor of adenosine deaminase) in an HD pharmacological model induced by 3-NPA in adult zebrafish. CPA, CGS 21680, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA were acutely administered via i.p. in zebrafish after 3-NPA (at dose 60 mg/kg) chronic treatment. Caffeine and ZM 241385 reversed the bradykinesia induced by 3-NPA, while CGS 21680 potentiated the bradykinesia caused by 3-NPA. Moreover, CPA, caffeine, ZM 241385, DPCPX, dipyridamole, and EHNA reversed the 3-NPA-induced memory impairment. Together, these data support the hypothesis that AR antagonists have an essential role in modulating locomotor function, whereas the activation of AR and blockade of AR and AR and modulation of adenosine levels may reduce the memory impairment, which could be a potential pharmacological strategy against late-stage symptoms HD.
亨廷顿病（HD）是一种神经退行性疾病，其特征为运动功能障碍、精神障碍和认知能力下降。在 HD 的早期，多巴胺 D 受体和腺苷 A 受体（AR）减少，而在晚期也会出现多巴胺 D 受体和腺苷 A 受体（AR）减少。腺苷在大脑中具有神经调节和神经保护作用，参与运动控制和记忆功能。3-硝基丙酸（3-NPA）是一种源自植物和真菌的毒素，可能会复制 HD 的行为表型和生化特征。本研究探讨了急性暴露于 CPA（AR 激动剂）、CGS 21680（AR 激动剂）、咖啡因（AR 和 AR 非选择性拮抗剂）、ZM 241385（AR 拮抗剂）、DPCPX（AR 拮抗剂）、双嘧达莫（核苷转运体抑制剂）和 EHNA（腺苷脱氨酶抑制剂）对 3-NPA 诱导的成年斑马鱼 HD 药理学模型的影响。CPA、CGS 21680、咖啡因、ZM 241385、DPCPX、双嘧达莫和 EHNA 在 3-NPA（剂量 60mg/kg）慢性处理后通过 i.p. 急性给予斑马鱼。咖啡因和 ZM 241385 逆转了 3-NPA 引起的运动迟缓，而 CGS 21680 增强了 3-NPA 引起的运动迟缓。此外，CPA、咖啡因、ZM 241385、DPCPX、双嘧达莫和 EHNA 逆转了 3-NPA 引起的记忆障碍。综上所述，这些数据支持了这样的假设，即 AR 拮抗剂在调节运动功能方面具有重要作用，而 AR 的激活和 AR 和 AR 的阻断以及腺苷水平的调节可能会减轻记忆障碍，这可能是一种针对 HD 晚期症状的潜在药物治疗策略。
