Kartik Shipra, Pal Rishi, Chaudhary Manju J, Nath Rajendra, Kumar Madhu
Department of Pharmacology and Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India.
Department of Physiology, Government Medical College, Tirwa Road, Kannauj, Lucknow, Uttar Pradesh, India.
Ann Neurosci. 2024 Oct;31(4):265-276. doi: 10.1177/09727531231191661. Epub 2023 Aug 27.
Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss, Lewy body build-up, and motor dysfunction. One of the primary pathogenic mechanisms of PD development is autophagy dysfunction and nitric oxide-mediated neurotoxicity.
The current study focuses on autophagy and nitric oxide (NO) signaling roles in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated PD mice and their protection by their modulators.
BALB/c mice were administered MPTP (30 mg/kg/i.p/day) for five consecutive days in order to create a PD model. Following MPTP poisoning, the doses of GA (16.8 mg/kg/day/i.p.), 7-nitroindazole (7-NI) (10 mg/kg/day/i.p.), and their combination were administered once daily for 14 days. Animals were observed for behavioral and locomotor changes, biochemical examination, inflammatory mediators, and analysis of molecular markers.
GA, 7-NI alone significantly reduced MPTP-induced locomotor, behavioral, and oxidative damage. Additionally, in MPTP-intoxicated animals, 7-NI and GA had protective effects on dopamine levels, TH positive DA neurons, inflammatory cytokines interleukin 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (Cox-2) concentration. Furthermore, GA increases LC3BII expression, which in turn increases autophagy. It also decreases total NO content, and a significant response of 7-NI demonstrates their interaction, which is neuroprotective.
Present research suggests that dysregulation of autophagy and NO-mediated neuroinflammation are involved in the pathogenesis and progression of MPTP-induced PD. The use of two pharmacotherapeutics, GA and 7-NI, respectively, significantly reduces MPTP-induced PD distortions and their interaction enhances the overall protective effect, suggesting that these pharmacological agents may be used for the treatment of PD.
帕金森病（PD）的特征是多巴胺能（DA）神经元丧失、路易小体形成和运动功能障碍。PD发生的主要致病机制之一是自噬功能障碍和一氧化氮介导的神经毒性。
本研究聚焦于自噬和一氧化氮（NO）信号在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒的PD小鼠中的作用以及其调节剂对它们的保护作用。
为建立PD模型，连续5天给BALB/c小鼠腹腔注射MPTP（30mg/kg/天）。MPTP中毒后，每天腹腔注射一次GA（16.8mg/kg/天）、7-硝基吲唑（7-NI）（10mg/kg/天）及其组合，持续14天。观察动物的行为和运动变化、生化检查、炎症介质以及分子标志物分析。
单独使用GA、7-NI可显著减轻MPTP诱导的运动、行为和氧化损伤。此外，在MPTP中毒的动物中，7-NI和GA对多巴胺水平、TH阳性DA神经元、炎性细胞因子白细胞介素1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、核因子-κB（NF-κB）和环氧合酶-2（Cox-2）浓度具有保护作用。此外，GA增加LC3BII表达，进而增加自噬。它还降低总NO含量，7-NI的显著反应表明它们之间的相互作用具有神经保护作用。
目前的研究表明，自噬失调和NO介导的神经炎症参与MPTP诱导的PD的发病机制和进展。分别使用两种药物GA和7-NI可显著减轻MPTP诱导的PD病变，它们的相互作用增强了整体保护作用，表明这些药物可能用于治疗PD。
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