alpha-synuclein and peoniflorin

Paeoniflorin, an active component of Radix Paeoniae Alba, has a neuroprotective effect in Parkinson's animal models. However, its mechanism of action remains to be determined.. In this study, we hypothesized that the neuroprotective effect of paeoniflorin occurs through the α-synuclein/protein kinase C δ subtype (PKC-δ) signaling pathway. We tested our hypothesis in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We evaluated the effects of paeoniflorin on the expression levels of signal components of the α-synuclein/PKC-δ pathway, cellular apoptosis and motor performance.. Our results demonstrated that paeoniflorin restored the motor performance impairment caused by MPTP, inhibited apoptosis, and protected the ultrastructure of neurons. Paeoniflorin treatment also resulted in the dose-dependent upregulation of an antiapoptotic protein, B-cell lymphoma-2, at the mRNA and protein levels, similar to the effects of the positive control, selegiline. In contrast, paeoniflorin treatment downregulated the expression of pro-apoptotic proteins BCL2-Associated X2, α-synuclein, and PKC-δ at the mRNA and protein levels, as well as the level of the activated form of nuclear factor kappa B (p-NF-κB p65).. Thus, our results showed that paeoniflorin exerts its neuroprotective effect by regulating the α-synuclein/PKC-δ signaling pathway to reduce neuronal apoptosis.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; Annexin A5; Anti-Inflammatory Agents, Non-Steroidal; Antiparkinson Agents; Apoptosis; Disease Models, Animal; Glucosides; Mice; Microscopy, Electron, Transmission; Monoterpenes; Neurotoxins; Parkinsonian Disorders; Protein Kinase C-delta; Rotarod Performance Test; Selegiline; Substantia Nigra

Acid-sensing ion channels (ASICs) are ligand-gated cation channels that respond to acidic stimuli. They are expressed throughout the mammalian nervous system. Complex subunit combinations and lack of specific blockers of native receptors result in the difficulty of resolving the functions of ASICs. In this study, we showed that rat pheochromocytoma cells (PC12 cells) functionally express ASICs with the activity of endogenous proton-gated conductance. PF is the principal active ingredient extracted from the root of Paeoniae alba, a Chinese herb commonly used to treat neurodegenerative disorders, especially PD. It was found that PF significantly up regulated the expression of LC3-II, which is specifically associated with autophagic vacuole membranes. PF also reduced the MPP(+) and acidosis-induced accumulation of α-synuclein, the major component of Lewy bodies. Moreover, PF was highly efficacious in modulating ASICs activity and protein expression. In addition, the data showed that PF was able to protect PC12 cells against MPP(+) and acidosis-induced cytotoxicity. In summary, these findings demonstrate for the first time that PF could enhance the autophagic degradation of α-synuclein by regulating the expression and activity of ASICs and thus produces protective effects against cytotoxicity. It also offers the experimental evidence for the potential role of ASICs in the pathogenesis of PD.

Topics: 1-Methyl-4-phenylpyridinium; Acid Sensing Ion Channels; Acidosis; alpha-Synuclein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Benzoates; Bridged-Ring Compounds; Cytoprotection; Glucosides; Microtubule-Associated Proteins; Monoterpenes; Nerve Tissue Proteins; Neurons; Parkinson Disease; PC12 Cells; Rats; Sodium Channels; Vacuoles