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

Abstract

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.