Long-term heat shock proteins (HSPs) induction by carbenoxolone improves hallmark features of Parkinson's disease in a rotenone-based model

•Oxidative stress in rotenone model of PD damages proteins resulting in aggregation.•Dysfunction of UPS leads to failure in removal of these protein aggregates.•HSPs induction by carbenoxolone prevents oxidative stress and protein modifications.•Up-regulation of HSPs restores activity of UPS and inhibits apoptosis.•Carbenoxolone induced HSP result in improvement of hallmark features of PD.

Protein aggregation and dysfunction of ubiquitin proteasome system (UPS) have been implicated in Parkinson's disease (PD) pathology for a long time. Heat shock proteins (HSPs) have neuro-protective effects in PD as they assist in protein refolding and targeting of irreparable proteins to UPS. To realize their benefits in a chronically progressing disease like PD, it is imperative to maintain slightly up-regulated levels of HSPs consistently over a longer period of time. Here, we evaluate the possible beneficial effects of HSP inducer carbenoxolone (cbx) in a rotenone-based rat model of PD.Simultaneously with rotenone, a low dose of cbx (20 mg/kg body weight) was administered for five weeks to male SD rats. Weekly behavioral analysis along with end-point evaluation of HSPs, UPS activity, apoptosis, and oxidative stress were performed. The activation of heat shock factor-1 (HSF-1) and up-regulation of HSP70, HSP40, and HSP27 levels in mid-brain following cbx administration resulted in the reduction of α-synuclein and ubiquitin aggregation. This decrease seems to be mediated by reduction in protein carbonylation as well as up-regulation of UPS activity. In addition, the decrease in apoptosis and oxidative stress following HSP upregulation prevented the decline in tyrosine hydroxylase (TH) and dopamine levels in mid-brain region, which in turn resulted in improved motor functions.Thus, persistent HSP induction at low levels by cbx could improve the PD pathophysiology.