Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali), 160062, Punjab, India.
Mol Neurobiol. 2022 Mar;59(3):1528-1542. doi: 10.1007/s12035-021-02711-4. Epub 2022 Jan 8.
Transient receptor potential melastatin-2 (TRPM2) channels are cation channels activated by oxidative stress and ADP-ribose (ADPR). Role of TRPM2 channels has been postulated in several neurological disorders, but, it has not been explored in animal models of Parkinson's disease (PD). Thus, the role of TRPM2 and its associated poly (ADPR) polymerase (PARP) signaling pathways were investigated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model using TRPM2 inhibitor, 2-aminoethyl diphenyl borinate (2-APB), and PARP inhibitor, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ-34). PD was induced by using a bilateral intranigral administration of MPTP in rats, and different parameters were evaluated. An increase in oxidative stress was observed, leading to locomotor and cognitive deficits in the PD rats. PD rats also showed an increased TRPM2 expression in the striatum and mid-brain accompanied by reduced expression of tyrosine hydroxylase (TH) in comparison to sham animals. Intraperitoneal administration of 2-APB and PJ-34 led to an improvement in the locomotor and cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and an increase in TH levels in the striatum and mid-brain. In addition, these pharmacological interventions also led to a decrease in the expression of TRPM2 in PD in the striatum and mid-brain. Our results provide a rationale for the development of potent pharmacological agents targeting the TRPM2-PARP pathway to provide therapeutic benefits for the treatment of neurological diseases like PD.
瞬时受体电位 melastatin-2（TRPM2）通道是一种阳离子通道，可被氧化应激和 ADP-核糖（ADPR）激活。TRPM2 通道的作用已被推测存在于几种神经紊乱中，但在帕金森病（PD）的动物模型中尚未得到探索。因此，本研究使用 TRPM2 抑制剂 2-氨基乙基二苯硼酸盐（2-APB）和聚（ADPR）聚合酶（PARP）抑制剂 N-（6-氧代-5,6-二氢苯并噻吩-2-基）-（N,N-二甲基氨基）乙酰胺盐酸盐（PJ-34），在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 大鼠模型中研究了 TRPM2 及其相关的 PARP 信号通路的作用。PD 通过在大鼠双侧黑质内注射 MPTP 诱导，评估了不同参数。结果发现氧化应激增加，导致 PD 大鼠运动和认知功能障碍。与假手术动物相比，PD 大鼠纹状体和中脑的 TRPM2 表达增加，而酪氨酸羟化酶（TH）的表达减少。与 MPTP 诱导的 PD 大鼠相比，腹腔内给予 2-APB 和 PJ-34 可改善运动和认知功能障碍。这些改善伴随着纹状体和中脑氧化应激水平的降低和 TH 水平的增加。此外，这些药物干预还导致 PD 大鼠纹状体和中脑 TRPM2 表达减少。我们的结果为开发针对 TRPM2-PARP 通路的有效药物提供了依据，为治疗 PD 等神经疾病提供了治疗益处。
