Neuroprotection Against MPP+-Induced Cytotoxicity Through the Activation of PI3-K/Akt/GSK3β/MEF2D Signaling Pathway by Rhynchophylline, the Major Tetracyclic Oxindole Alkaloid Isolated From Uncaria rhynchophylla

Abstract

Rhynchophylline is a major tetracyclic oxindole alkaloid in Uncaria rhynchophylla, which has been extensively used as traditional herb medicine for the prevention of convulsions and hypertension. However, there is still little evidence about the neuroprotective effects of rhynchophylline for Parkinson’s disease (PD), a neurodegenerative condition currently without any effective cure. In this present study, the neuroprotective molecular mechanisms of rhynchophylline were investigated in a cellular model associated with PD. It is shown that rhynchophylline (10–50 μM) greatly prevented neurotoxicity caused by 1-methyl-4-phenylpyridinium ion (MPP+) in primary cerebellar granule neurons, as evidenced by the promotion of cell viability as well as the reversal of dysregulated protein expression of Bax/Bcl-2 ratio. Very encouragingly, we found that rhynchophylline markedly enhanced the activity of the transcription factor myocyte enhancer factor 2D (MEF2D) at both basal and pathological conditions using luciferase reporter gene assay, and reversed the inhibition of MEF2D caused by MPP+. Additionally, pharmacological inhibition of PI3-Kinase or short hairpin RNA-mediated gene down-regulation of MEF2D abrogated the protection provided by rhynchophylline. Furthermore, Western blot analysis revealed that rhynchophylline could potentiate PI3-K/Akt to attenuate GSK3β (the MEF2D inhibitor) in response to MPP+ insult. In conclusion, rhynchophylline inhibits MPP+-triggered neurotoxicity by stimulating MEF2D via activating PI3-K/Akt/GSK3β cascade. Rhynchophylline is served as a novel MEF2D enhancer and might be a potential candidate for further preclinical study in the prevention of PD.

Neuroprotection Against Parkinson’s Disease Through the Activation of Akt/GSK3β Signaling Pathway by Tovophyllin A

“…Akt inhibits GSK-3β function via phosphorylation at serine residue (Ser9 of GSK-3β) and thereby reduces apoptosis (Golpich et al, 2015;Norwitz et al, 2019). In our study, we found that MPTP decreased Akt activity and increased of GSK-3β function, consistent with previous studies (Hu et al, 2018). Remarkably, TA pre-treatment abolished MPTP-induced changes and increased p-Akt/Akt ratio while decreasing GSK-3β activity in mice.…”

“…Akt is mainly activated by PI3K, and this pathway promotes cell survival and cytoprotection by phosphorylating various enzymes, including antioxidant proteins and pro-apoptotic regulators, as well as some transcription factors (Nakano et al, 2017;Yue et al, 2017). Inhibition of this cascade is correlated with neurodegeneration, particularly in PD (Hu et al, 2018). GSK-3 is involved in an array of progresses, such as metabolism, gene expression, proliferation and cell survival.…”

Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

“…Taken together, all these findings suggest that Uncaria rhynchophylla display neuroprotective action in protecting neuronal damage through multiple pathways which could be due to the beneficial effect of active compounds as well as the combination effect of those compounds present in Uncaria rhynchophylla. Several studies have reported on the neuroprotective effect of alkaloid in Uncaria rhynchophylla such as hirsutine [187], rhynchophylline [188][189][190][191], and isorhynchophylline [192][193][194][195].…”

Comparative transcriptomic analysis revealed novel potential therapeutic targets of traditional Chinese medicine (Pinggan-Qianyang decoction) on vascular remodeling in spontaneously hypertensive rats

“…Gastrodin inhibits PDGF-BB induced VSMC migration, its mechanisms may be associated with the inhibition of the JNK signaling pathway activation [ 55 ]. The rhynchophylline can inhibite MPP + -triggered neurotoxicity by stimulating MEF2D via activating PI3-K/Akt/GSK3β signaling pathway [ 56 ].…”