Li Yang, Yin Qiao, Wang Bing, Shen Tingting, Luo Weifeng, Liu Tong
Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Neurology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, China.
Front Pharmacol. 2022 Oct 12;13:944376. doi: 10.3389/fphar.2022.944376. eCollection 2022.
Reserpine is an effective drug for the clinical treatment of hypertension. It also induces Parkinson's disease (PD)-like symptoms in humans and animals possible through the inhibition of monoamine vesicular transporters, thus decreasing the levels of monoamine neurotransmitters in the brain. However, the precise mechanisms remain unclear. Herein, we aimed to develop a preclinical reserpine model recapitulating the non-motor and motor symptoms of PD and investigate the underlying potential cellular mechanisms. Incubation of reserpine induced apoptosis, led to the accumulation of intracellular reactive oxygen species (ROS), lowered DNA methylation of alpha-synuclein gene, resulted in alpha-synuclein protein deposition, and elevated the ratio of LC3-II/LC3-Ⅰ and p62 in cultured SH-SY5Y cells. Feeding reserpine dose-dependently shortened the lifespan and caused impairment of motor functions in male and female Drosophila. Moreover, long-term oral administration of reserpine led to multiple motor and non-motor symptoms, including constipation, pain hypersensitivity, olfactory impairment, and depression-like behaviors in mice. The mechanistic studies showed that chronic reserpine exposure caused hypomethylation of the alpha-synuclein gene and up-regulated its expression and elevated the ratio of LC3-II/LC3-Ⅰ and expression of p62 in the substantia nigra of mice. Thus, we established preclinical animal models using reserpine to recapitulate the motor and non-motor symptoms of PD. Chronic reserpine exposure epigenetically elevated the levels of alpha-synuclein expression possible by lowering the DNA methylation status and inducing autophagic impairment and .
利血平是临床上治疗高血压的有效药物。它还可能通过抑制单胺囊泡转运体，在人和动物中诱发帕金森病（PD）样症状，从而降低大脑中单胺神经递质的水平。然而，确切机制仍不清楚。在此，我们旨在建立一个临床前利血平模型，重现PD的非运动和运动症状，并研究潜在的细胞机制。利血平孵育诱导细胞凋亡，导致细胞内活性氧（ROS）积累，降低α-突触核蛋白基因的DNA甲基化，导致α-突触核蛋白蛋白沉积，并提高培养的SH-SY5Y细胞中LC3-II/LC3-Ⅰ和p62的比例。给果蝇喂食利血平剂量依赖性地缩短了寿命，并导致运动功能受损。此外，长期口服利血平导致小鼠出现多种运动和非运动症状，包括便秘、疼痛超敏、嗅觉障碍和抑郁样行为。机制研究表明，长期暴露于利血平会导致小鼠黑质中α-突触核蛋白基因的低甲基化，上调其表达，并提高LC3-II/LC3-Ⅰ的比例和p62的表达。因此，我们使用利血平建立了临床前动物模型，以重现PD的运动和非运动症状。长期暴露于利血平可能通过降低DNA甲基化状态和诱导自噬损伤，在表观遗传上提高α-突触核蛋白的表达水平。
