Paeoniflorin Ameliorates Cognitive Impairment in Parkinson’s Disease via JNK/p53 Signaling

Abstract

Paeoniflorin (PF) has numerous benefits, including anti-inflammatory and anti-apoptosis effects. It also exhibits neuroprotective effects in Alzheimer’s disease (AD) via the ROS-JNK-p53 pathway. However, it is not clear if it has neuroprotective effects against cognitive impairment in Parkinson’s disease (PD). Through network pharmacology, we identified probable targets as well as signal pathways through which PF might affect cognitive impairment in PD. Then, we experimentally validated our findings. The core genes of the PPI network include MAPK8 (JNK), TP53, CASP3 (caspase-3), protein-95 (PSD95), and SYN. Pathway enrichment analysis revealed that genes involved in apoptosis and 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 MPTP-induced neuronal injury by inhibiting apoptosis in hippocampal neurons of the CA1 and CA3, and upregulating postsynaptic density PSD95 as well as synaptophysin (SYN) protein levels. Similar protective effects were observed upon JNK/p53 pathway inhibition using SP600125. Overall, PF improved cognitive impairment in PD by inhibiting JNK/p53 signaling pathway.