title: Inhibition of endoplasmic reticulum stress is involved in the neuroprotective effects of candesartan cilexitil in the rotenone rat model of Parkinson's disease.
abstract: Recent studies indicated that angiotensin II (Ang II) receptor blockers could reduce neurotoxins-induced dopaminergic (DA) cell death, but the underlying mechanisms are still unclear. Given that endoplasmic reticulum (ER) stress plays a major role in rotenone-induced neuronal apoptosis, we investigated whether candesartan cilexetil, a selective and high-affinity Ang II receptor antagonist, could protect the DA neuron via reducing ER stress in a chronic rotenone rat model for Parkinson's disease (PD). Our data showed that candesartan cilexetil could ameliorate the descent latency in catalepsy tests, and decrease rotenone-induced DA neuron apoptosis. Moreover, candesartan cilexetil has been found to play a protective role via down-regulating the expression of activating transcription factor 4 (ATF4), the CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), and p53 upregulated modulator of apoptosis (Puma). Thus, our experiments strongly suggest that administration of candesartan cilexetil protects DA neuron involving blocking ER stress, possibly via inhibiting activation of the ATF4-CHOP-Puma pathway, which could provide new insight into clinical therapeutics for PD.
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wu
authors.forename: You-Yong
authors.initials: YY
authors.lastname: Tian
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Shi
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone; D013777:Tetrazoles / Q000008:administration & dosage*; D014475:Uncoupling Agents
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D013777:Tetrazoles; D014475:Uncoupling Agents; D012402:Rotenone; C077793:candesartan cilexetil
keywords: Ang II; Apoptosis; Candesartan cilexetil; DA; Dopamine; ER; ER stress; PD; Parkinson's disease; Rotenone; SNc; UPR; angiotensin II; dopaminergic; endoplasmic reticulum; substantia nigra pars compacta; unfolded protein response