Mitochonic acid 5 ameliorates the motor deficits in the MPTP-induced mouse Parkinson’s disease model by AMPK-mediated autophagy

Abstract

Parkinson's disease (PD) is a well-known neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, and oxidative stress and neuroinflammation are also associated with the pathogenesis of PD. Mitochonic acid 5 , an analogue of indole-3-acetic acid, exerts key protective roles in inhibiting apoptosis, oxidative stress and neuroinflammation in multiple diseases. However, whether MA-5 can be beneficial for PD remains unclear. Hence, the aim of this study was to investigate the neuroprotective role of MA-5 in PD. In the current study, MPTP-challenged mice were treated as the in vivo model, and the effect of MA-5 on the motor function, neuronal survival, oxidative stress, neuroinflammation and the underlying mechanisms involved with AMPK and autophagy were determined. We revealed that MA-5 obviously up-regulated the phosphorylation of AMPK and promoted the autophagy (indicated by the increased LC3II/LC3I, parkin, pink and decreased p62) in substantia nigra (SN), ameliorated the motor deficits, up-regulated the expression of TH, suppressed the inflammation (indicated by the decreased protein levels of interleukin (IL)-1β, IL-6, tumour necrosis factor α) in SN in MPTP-induced mice. However, these patterns were reversed after the treatment of Compound C, an inhibitor of AMPK; also, after the application of CSA, an inhibitor of autophagy, MA-5 cannot play against the neurotoxicity of MPTP in mice. These combined results suggest that MA-5 can protect against MPTP-induced neurotoxicity to ameliorate the impaired motor function, which may be modulated via activation of AMPK-induced autophagy.

Autophagy‑regulating miRNAs: Novel therapeutic targets for Parkinson's disease (Review)

“…Besides, AMPK-mediated autophagy is also associated with the progression of Pd. In both MPTP and rotenone-induced mouse models of Pd, it has been discovered that the activation of AMPK-mediated autophagy by several compounds, including mitochonic acid 5 and α-mangostin, ameliorate α-synuclein aggregation, oxidative stress, neuroinflammation, neuronal degeneration and motor deficits (28,29). Moreover, inhibitors of AMPK and autophagy counteract these effects, indicating the neuroprotection of AMPK-activated autophagy in Pd (28,29).…”

“…In both MPTP and rotenone-induced mouse models of Pd, it has been discovered that the activation of AMPK-mediated autophagy by several compounds, including mitochonic acid 5 and α-mangostin, ameliorate α-synuclein aggregation, oxidative stress, neuroinflammation, neuronal degeneration and motor deficits (28,29). Moreover, inhibitors of AMPK and autophagy counteract these effects, indicating the neuroprotection of AMPK-activated autophagy in Pd (28,29). Targeting the AMPK/mTOR signaling pathway to inhibit excessive autophagy induced by 6-OHdA alleviates neuronal death, exerting a neuroprotective effect on Pd (30).…”