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.
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.
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.