Fig. 6: Withaferin A has multiple neuroprotective effects; Withaferin A and amantadine may treat PD by suppressing STING.

A Hierarchical clustered heatmap of gene expression profiles for WA, amantadine, Ve, ganciclovir treatment in SNc of MPTP-induced PD mice. B The heatmap of DEGs of MPTP-received mice treated with WA, amantadine, Ve, ganciclovir. C Venn diagram of overlapping significantly changed genes (±1.2 fold, P < 0.05). D Scatter plot highlights the DEGs of amantadine, Ve and GCV treatment compared with vehicle in MPTP-recieved mice, significantly altered genes are colored in red. (P < 0.05 with Benjamini–Hochberg multiple testing correction). E The pharmacological actions of WA, amantadine, Ve and GCV from published literatures. F Gene Ontology enrichment was based on DEGs that have a P value smaller than 0.05. G Spearman correlation between aggregated response of WA, amantadine, Ve and GCV gene signatures to different interventions. H Network of interventions based on similarity of their gene expression profiles. The width of edge is defined by statistical significance of Spearman correlation between interventions. Only significant connections are shown. I Relative mRNA levels in SNc of WA, amantadine, Ve and GCV treated mice. Data are mean ± s.e.m.; n = 9 biologically independent animals; *P < 0.05, **P < 0.01, and ***P < 0.001 by one-way ANOVA with Bonferroni’s post hoc test. J, K Time to traverse beam apparatus, time to descend pole, hind-limb clasping reflex score, fall latency from an accelerating rotarod and gait analysis. Data are mean ± s.e.m.; n = 9 biologically independent animals. The one-way ANOVAs were used for statistical analysis followed by Bonferroni’s post hoc test. *P < 0.05, **P < 0.01, and ***P < 0.001. L Schematic summary of the mechanism underlying the neuroprotective actions of WA in PD. The neuroprotective role of WA against PD is dependent on relief of oxidative stress, mitigation of the STING-mediated neuroinflammation, enhancement of mitochondrial function, and reduction of apoptosis, through activation of DJ1-Nrf2-STING axis in dopaminergic neurons of SNc.