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

Background: 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.

Purpose: 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.

Method: 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.

Results: 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.

Conclusion: 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.