Modulation of Autophagy and Nitric Oxide Signaling via Glycyrrhizic Acid and 7-Nitroindazole in MPTP-induced Parkinson’s Disease Model

IF 1.8 Q4 NEUROSCIENCES Annals of Neurosciences Pub Date : 2023-08-27 DOI:10.1177/09727531231191661
S. Kartik, Rishi Pal, M. Chaudhary, R. Nath, M. Kumar
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Abstract

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.
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通过甘草酸和7-硝基吲唑调节MPTP诱导的帕金森病模型中的自噬和一氧化氮信号传导
帕金森病(PD)的特点是多巴胺能(DA)神经元丧失、路易体形成和运动功能障碍。PD发展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。目前的研究重点是1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)中毒PD小鼠的自噬和一氧化氮(NO)信号传导作用及其调节剂的保护作用。对BALB/c小鼠连续5天给予MPTP(30mg/kg/i.p/天)以建立PD模型。MPTP中毒后,GA(16.8 mg/kg/天/i.p.)、7-硝基吲唑(7-NI)(10 mg/kg/天/ip.)及其组合的剂量每天给药一次,持续14天。观察动物的行为和运动变化、生化检查、炎症介质和分子标记物分析。单独的GA、7-NI显著降低了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增加了LC3BII的表达,进而增加了自噬。它还降低了总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,自噬和NO介导的神经炎症的失调参与了MPTP诱导的PD的发病机制和进展。分别使用GA和7-NI两种药物疗法,显著减少了MPTP诱发的PD扭曲,它们的相互作用增强了整体保护作用,提示这些药物可以用于治疗PD。
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来源期刊
Annals of Neurosciences
Annals of Neurosciences NEUROSCIENCES-
CiteScore
2.40
自引率
0.00%
发文量
39
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