title: 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.
authors.affiliation: Department of Biophysics, Panjab University, Chandigarh 160014, India. Electronic address: poonamthkur@gmail.com.
authors.forename: Poonam
authors.initials: P
authors.lastname: Thakur
authors.affiliation: Department of Biophysics, Panjab University, Chandigarh 160014, India. Electronic address: bnehru@pu.ac.in.
authors.forename: Bimla
authors.initials: B
authors.lastname: Nehru
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002229:Carbenoxolone / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone; D014157:Transcription Factors / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D051844:alpha-Synuclein; D012402:Rotenone; D014446:Tyrosine 3-Monooxygenase; D002229:Carbenoxolone; D004298:Dopamine
keywords: Oxidative stress; Protein aggregation; Protein carbonylation; Ubiquitin proteasome system; α-Synuclein