peoniflorin and Parkinson-Disease

Parkinson's disease (PD) is a degenerative neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. The loss of the dopaminergic projection from the SNpc deprives the striatum of dopamine and results in a myriad of motor signs, including tremor, rigidity and ataxia. Although the stimulus for the initiation of the degenerative process is not understood, 80% of the dopaminergic neurons in the SNpc must be lost before the clinical symptoms of the disease are observed. This suggests that the degenerative process is initiated many years before clinical presentation of the disease. The neurodegeneration observed in PD is accompanied by inflammatory processes, and it has been suggested that anti-inflammatory drugs may be useful in slowing disease progression once the clinical signs of PD have been observed. This review summarizes and evaluates the progress that has been made in this area of research since 2006.

Topics: Animals; Anti-Inflammatory Agents; Benzoates; Bridged-Ring Compounds; Diterpenes; Drug Evaluation, Preclinical; Glucosides; Humans; Inflammation; Monoterpenes; Parkinson Disease; Phenanthrenes; Purines

This study aimed to explore the neuroprotective effects of paeoniflorin on oxidative stress and apoptosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mice.. The effects of paeoniflorin on motor function in mice were evaluated by behavioral test. Then substantia nigra of mice were collected and neuronal damage was assessed using Nissl staining. Positive expression of tyrosine hydroxylase (TH) was detected by immunohistochemistry. Levels of malondialdehyde, superoxide dismutase (SOD) and glutathione were measured by biochemical method. terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay was used to detect apoptosis of dopaminergic neurons. Western blotting and real-time fluorescence quantitative PCR were used to detect the protein and mRNA expressions of Nrf2, heme oxygenase-1 (HO-1), B-cell lymphoma-2(Bcl-2), Bax and cleaved caspase-3.. Paeoniflorin treatment significantly ameliorated the motor performance impairment in MPTP-induced PD mice. Moreover, it notably increased the positive expression rate of TH and reduced the damage and apoptosis of dopaminergic neurons in the substantia nigra. Furthermore, paeoniflorin increased the levels of SOD and glutathione and decreased the malondialdehyde content. It also promoted Nrf2 nuclear translocation, increased the protein and mRNA expressions of HO-1 and Bcl-2 and reduced the protein and mRNA expressions of BCL2-Associated X2 (Bax) and cleaved caspase-3. Treatment with the Nrf2 inhibitor, ML385, notably reduced the effects of paeoniflorin in MPTP-induced PD mice.. Neuroprotective effects of paeoniflorin in MPTP-induced PD mice may be mediated via inhibition of oxidative stress and apoptosis of dopaminergic neurons in substantia nigra through activation of the Nrf2/HO-1 signaling pathway.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Heme Oxygenase-1; Mice; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Parkinson Disease; RNA, Messenger; Signal Transduction

Paeoniflorin (PF) has numerous benefits, including anti-inflammatory and anti-apoptosis effects. However, it is not clear if it has neuroprotective effects against cognitive impairment (CI) in Parkinson's disease (PD). Through network pharmacology, we identified probable targets as well as signal pathways through which PF might affect CI in PD. Then, we experimentally validated our findings. The core genes of the protein-protein interactions (PPI) network include MAPK8 (JNK), TP53, CASP3 (caspase-3), postsynaptic density protein-95 (PSD-95) and synaptophysin (SYN). Pathway enrichment analysis revealed that genes involved in apoptosis and mitogen-activated protein kinase (MAPK) signaling were significantly enriched. Because JNK is a key mediator of p53-induced apoptosis, we wondered if JNK/p53 pathway influences the effects of PF against apoptosis in mouse model of PD. Molecular docking analysis showed that PF had good affinity for JNK/p53. The results of the experiments indicated that PF ameliorated behavioral impairments and upregulated the expression of the dopamine (DA) neurons, suppressed cell apoptosis in substantia nigra pars compacta (SNpc) of PD. Additionally, PF improved 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal injury by inhibiting apoptosis in hippocampal neurons of the CA1 and CA3, and upregulating PSD-95 as well as SYN protein levels. Similar protective effects were observed upon JNK/p53 pathway inhibition using SP600125. Overall, PF improved CI in PD by inhibiting JNK/p53 pathway.

Topics: Animals; Cognitive Dysfunction; Dopaminergic Neurons; Glucosides; Mice; Molecular Docking Simulation; Monoterpenes; Parkinson Disease; Signal Transduction; Tumor Suppressor Protein p53

Paeoniflorin (PF) is the main active component extracted from the roots of Paeonialactiflora, a traditional Chinese medicine used for the treatment of neurodegenerative disorders, especially Parkinson's disease (PD). The degeneration of dopaminergic (DA-) neurons in PD may be caused by pathological activation of acid-sensing ion channels (ASICs). Thus, we designed a series of experiments to evaluate the therapeutic effects of PF and to test whether its effects are related to its inhibitory effect on ASIC1a. We found that systemic administration of PF or ASICs blockers (psalmotoxin-1 and amiloride) improved behavioral symptoms, delayed DA-neuronal loss and attenuated the reduction of dopamine (DA) and its metabolites in a rat model of 6-hydroxydopamine (6-OHDA)-induced PD. In addition, our data showed that PF, like ASICs blockers, regulated the expression of ASIC1a, decreased the level of α-synuclein (α-SYN), and improved autophagic dysfunction. Further experiments showed that ASIC1a knockdown down-regulated the α-SYN level and alleviated the autophagic injury in the 6-OHDA-treated ASIC1a-silenced PC12 cells. In summary, these findings indicate that PF enhanced the autophagic degradation of α-SYN and, thus, protected DA-neurons against the neurotoxicity caused by 6-OHDA. These findings also provide experimental evidence that PF may be a neuroprotectant for PD by acting on ASIC1a and that ASIC1a may be involved in the pathogenesis of PD.

Topics: Acid Sensing Ion Channels; Animals; Autophagy; Bridged-Ring Compounds; Dopamine; Dopaminergic Neurons; Glucosides; Male; Monoterpenes; Neuroprotective Agents; Oxidopamine; Parkinson Disease; PC12 Cells; Rats; Rats, Sprague-Dawley

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