Compound Dihuang Granule Changes Gut Microbiota of MPTP-Induced Parkinson's Disease Mice via Inhibiting TLR4/NF-κB Signaling.

Intestinal microbiota was connected to Parkinson's Disease (PD) pathology. The ancient Chinese medication for PD is Compound Dihuang Granule (CDG), and we found a neuroprotective function in treating the constipation of PD patients. Nevertheless, the mechanism of action still needs to be clarified. We predicted the probable targets of CDG against PD through Traditional Chinese medicine (TCM) network pharmacology and verified the analysis through animal experiments in vivo. The protein-protein interaction (PPI) network analysis screened PD-related genes, including Toll-like receptor 4(TLR4), TANK-binding kinase 1(TBK1), Nuclear Factor- Kappa B (NF-κB), and Tumor necrosis factor (TNF). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses proved that the NF-κB and toll-like receptor signaling pathways serve a key function in CDG therapy of PD. Molecular docking analysis demonstrated that CDG strongly connected to TLR4/NF-κB. Experiments findings indicated that CDG improved the damage of dopaminergic neurons and gut microbial dysbiosis, ameliorated motor impairments, and suppressed the PD-associated inflammation and oxidative stress in mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahy dropyridine (MPTP). CDG suppressed the inflammatory proteins in the colon and protected the intestinal barrier. Overall, CDG improved gut microbial in PD by blocking the pathway of TLR4/NF-κB.

Paeoniflorin ameliorates cognitive impairment in Parkinson's disease via JNK/p53 signaling.

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.