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. 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.

Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson’s Disease

“…CA3, and upregulates PSD-95 as well as SYN protein levels. Similar protective effects were observed upon JNK/p53 pathway inhibition using SP600125[73].MadecassosideCentella asiatica 15, 30, 60 mg/kg MPTP-induced ratsReversing the depletion of DA, antioxidant activity, increasing ratio of Bcl-2/Bax, increasing protein expression of BDNF[74].LoganinCornus officinalis fruits 50 mg/kg MPTP-induced mice Reduce inflammation, autophagy, and apoptosis[75].…”

Serum metabolomics analysis combined with network pharmacology reveals possible mechanisms of postoperative cognitive dysfunction in the treatment of Mongolian medicine Eerdun Wurile basic formula

“…Studies have shown that EP300 acetylates SIRT2 and indirectly increases the transcriptional activity of p53/TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (Han et al, 2008). In contrast, activation of the p53 pathway causes cognitive dysfunction, and dexmedetomidine and paeoniflorin attenuate cognitive dysfunction by inhibiting the p53 pathway (He et al, 2022; Li et al, 2022; Wang, Zhang, & Cai, 2021). Furthermore, EP300 can enhance FOXO1 transcriptional activity by acetylation (Perrot & Rechler, 2005), thus alleviating sevoflurane‐induced cognitive impairment (Yang et al, 2022).…”

The effect of paeoniflorin on the rewarding effect of METH and the associated cognitive impairment in mice

“…Although it is not clear how PF affects the expression of PSD-95 and SYP in METH-induced mice, studies have shown that PF can improve 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cognitive impairment in mice by inhibiting the expression of dopaminergic neurons in the JNK/p53 signaling pathway and apoptosis in Hip. It upregulating the expression of PSD-95 and SYP (He ZQ et al, 2022 Apr). Studies have also shown that PF enhances neuronal survival through the ERK/CREB signaling pathway and inhibits N-methyl-Daspartate (NMDA) -induced neurotoxicity (Ip FC et al, 2016 Nov 4).…”