title: Inhibition of endoplasmic reticulum stress-activated IRE1α-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rat model of Parkinson's disease.
abstract: Telmisartan, one unique angiotensin II type 1 receptor blocker, has been attracting attention due to its putative peroxisome proliferator-activated receptor (PPAR)-γ or β/δ actions. Recently, telmisartan has been reported to exert neuroprotective effects in animal models of Parkinson's disease (PD). However, the underlying mechanisms have not been fully clarified. Recently, accumulating evidence has shown that endoplasmic reticulum (ER) stress plays a crucial role in rotenone-induced neuronal apoptosis. Additionally, studies have revealed that inositol-requiring enzyme/endonuclease 1α (IRE1α) is necessary and sufficient to trigger ER stress. In the present study, we aimed to determine whether ER stress-activated IRE1α-mediated apoptotic pathway is involved in the neuroprotection of telmisartan in the rotenone rats of PD and explore the possible involvement of PPAR-β/δ activation. The catalepsy tests were performed to test the catalepsy symptom. The dopamine content and α-synuclein expression were ascertained through high-performance liquid chromatography and immunohistochemistry, respectively. The expression of IRE1α, TNF receptor associated factor 2 (TRAF2), caspase-12 and PPAR-β/δ was detected by western blot. Neuronal apoptosis was assessed by TUNEL and immunohistochemistry. Our results show that telmisartan ameliorated the catalepsy symptom and attenuated dopamine depletion as well as α-synuclein accumulation. Moreover, telmisartan decreased ER stress-mediated neuronal apoptosis. Furthermore, telmisartan inhibited IRE1α-TRAF2-caspase-12 apoptotic signaling pathway. Additionally, telmisartan activated PPAR β/δ, implying that PPAR-β/δ activation properties of telmisartan are possibly or partially involved in the neuroprotective effects. In conclusion, our findings suggest that suppressing ER stress-activated IRE1α-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rats of PD.
authors.affiliation: Department of Geriatrics, Huai'an First People's Hospital, Nanjing Medical University, P.O. Box 223300, No. 6 Beijing Road West, Huai'an, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Ou
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China. Electronic address: zhangyingdong@aliyun.com.
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, P.O. Box 211166, No. 818 Tianyuan East Road, Jiangning dist., Nanjing, PR China. Electronic address: dyzhu@njmu.edu.cn.
authors.forename: Dongya
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D053454:Caspase 12 / Q000378:metabolism*; D002375:Catalepsy / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D047494:PPAR delta / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D000077333:Telmisartan
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; C575026:Ern1 protein, rat; D009097:Multienzyme Complexes; D018696:Neuroprotective Agents; D047494:PPAR delta; D048068:PPAR-beta; D047992:TNF Receptor-Associated Factor 2; D012402:Rotenone; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D053454:Caspase 12; D000077333:Telmisartan; D004298:Dopamine
keywords: Apoptosis; Inositol-requiring enzyme 1α; Parkinson's disease; Peroxisome proliferator-activated receptor-β/δ; Telmisartan