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.
Highlights
Parkinson’s disease (PD) is the 2nd most prevalent neurodegenerative disorder after Alzheimer's disease (AD) (Xicoy et al 2020). cognitive impairment (CI) is a prevalent nonmotor symptom of PD (Santangelo et al 2015)
A total of 9489 PD-associated genes were identified from the online disease database (Figure 1A, Supplementary File S2)
The affinities of JNK, p53, PSD95, and SYN for PF were -5.44, -5.64, -6.38, and - 5.77 kcal/ mol, suggesting good binding affinities. These findings show that PF exerts neuroprotective effects by inhibiting apoptosis and highlight mitogen-activated protein kinase (MAPK) signaling as a potential therapeutic target. p53, a target of MAPK signaling, is a crucial mediator of normal cell differentiation and survival
Summary
Parkinson’s disease (PD) is the 2nd most prevalent neurodegenerative disorder after Alzheimer's disease (AD) (Xicoy et al 2020). cognitive impairment (CI) is a prevalent nonmotor symptom of PD (Santangelo et al 2015). Dopaminergic neurons in substantia nigra and ventral tegmental area project to the hippocampal region through midbrain and cortex dopamine system pathway (Espadas et al 2021). Dopaminergic projection to hippocampus participates in cognitive function in PD (Jokinen et al 2009). The CA1 region of the hippocampus is involved in cognitive processes, learning, and memory (Li et al 2020), and which along with CA3, forms the hippocampal Schaffer collateral pathway, is one of the most studied hippocampal synaptic pathway (Zamora-Moratalla and Martín 2021). When dopaminergic neurons in the ventral tegmental areas and substantia nigra are damaged, causes a reduction of the direct dopaminergic projections. This could eventually result in reduced levels of neurogenesis and synaptic plasticity in hippocampus
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