Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil; Sorbonne Universités UPMC UMR S 1127, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil.
Brain Behav Immun. 2018 Nov;74:241-251. doi: 10.1016/j.bbi.2018.09.014. Epub 2018 Sep 11.
The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms. Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics. The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors. The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect. Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol. Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662. In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.
长期使用降低多巴胺能神经传递的药物会导致一种称为迟发性运动障碍（TD）的多动性运动障碍。这种疾病的病理生理学尚未完全了解，但可能涉及氧化和神经炎症机制。大麻素（CBD）是大麻植物中存在的主要非致幻化合物，可能是治疗 TD 的一种可行的治疗选择。这种植物大麻素具有抗氧化、抗炎和抗精神病特性，并降低经典抗精神病药的急性运动作用。本研究调查了 CBD 是否会减轻慢性给予氟哌啶醇引起的小鼠口面部运动障碍、氧化应激和炎症变化。此外，我们在体内和体外（在原代小胶质细胞培养物中）验证了这些作用是否由 PPARγ 受体介导。结果表明，每天用氟哌啶醇治疗 21 天的雄性瑞士小鼠会出现口面部运动障碍。在每次氟哌啶醇注射前给予 CBD 可预防这种作用。用氟哌啶醇治疗的小鼠在纹状体中显示小胶质细胞激活和炎症介质增加。这些变化也被 CBD 减少。另一方面，接受 CBD 和氟哌啶醇的动物纹状体中的抗炎细胞因子 IL-10 水平增加。关于氧化应激，氟哌啶醇诱导脂质过氧化并降低过氧化氢酶活性。这种后者的作用被 CBD 减弱。CBD 和氟哌啶醇的组合还增加了 PPARγ 受体的共激活因子 PGC-1α mRNA 的表达。用 PPARγ 拮抗剂 GW9662 预处理阻断了 CBD 在我们的 TD 模型中的行为作用。CBD 还阻止了 LPS 刺激的小胶质细胞激活，该作用也被 GW9662 拮抗。总之，我们的结果表明，CBD 通过激活 PPARγ 受体并减轻纹状体中的神经炎症变化，可预防氟哌啶醇引起的口面部运动障碍。
