PMID- 26879867 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20211203 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 776 DP - 2016 Apr 5 TI - Inhibition of endoplasmic reticulum stress-activated IRE1alpha-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rat model of Parkinson's disease. PG - 106-15 LID - S0014-2999(16)30064-4 [pii] LID - 10.1016/j.ejphar.2016.02.042 [doi] AB - Telmisartan, one unique angiotensin II type 1 receptor blocker, has been attracting attention due to its putative peroxisome proliferator-activated receptor (PPAR)-gamma or beta/delta 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 1alpha (IRE1alpha) is necessary and sufficient to trigger ER stress. In the present study, we aimed to determine whether ER stress-activated IRE1alpha-mediated apoptotic pathway is involved in the neuroprotection of telmisartan in the rotenone rats of PD and explore the possible involvement of PPAR-beta/delta activation. The catalepsy tests were performed to test the catalepsy symptom. The dopamine content and alpha-synuclein expression were ascertained through high-performance liquid chromatography and immunohistochemistry, respectively. The expression of IRE1alpha, TNF receptor associated factor 2 (TRAF2), caspase-12 and PPAR-beta/delta 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 alpha-synuclein accumulation. Moreover, telmisartan decreased ER stress-mediated neuronal apoptosis. Furthermore, telmisartan inhibited IRE1alpha-TRAF2-caspase-12 apoptotic signaling pathway. Additionally, telmisartan activated PPAR beta/delta, implying that PPAR-beta/delta activation properties of telmisartan are possibly or partially involved in the neuroprotective effects. In conclusion, our findings suggest that suppressing ER stress-activated IRE1alpha-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rats of PD. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Tong, Qiang AU - Tong Q AD - 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. FAU - Wu, Liang AU - Wu L AD - Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China. FAU - Jiang, Teng AU - Jiang T AD - Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China. FAU - Ou, Zhou AU - Ou Z AD - Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, PR China. FAU - Zhang, Yingdong AU - Zhang Y AD - 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. FAU - Zhu, Dongya AU - Zhu D AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160212 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Benzimidazoles) RN - 0 (Benzoates) RN - 0 (Ern1 protein, rat) RN - 0 (Multienzyme Complexes) RN - 0 (Neuroprotective Agents) RN - 0 (PPAR delta) RN - 0 (PPAR-beta) RN - 0 (TNF Receptor-Associated Factor 2) RN - 03L9OT429T (Rotenone) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 3.1.- (Endoribonucleases) RN - EC 3.4.22.- (Caspase 12) RN - U5SYW473RQ (Telmisartan) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Benzimidazoles/*pharmacology/therapeutic use MH - Benzoates/*pharmacology/therapeutic use MH - Caspase 12/*metabolism MH - Catalepsy/complications/drug therapy MH - Disease Models, Animal MH - Dopamine/metabolism MH - Endoplasmic Reticulum Stress/*drug effects MH - Endoribonucleases/metabolism MH - Enzyme Activation/drug effects MH - Male MH - Multienzyme Complexes/metabolism MH - Neostriatum/drug effects/metabolism/pathology MH - Neuroprotective Agents/pharmacology/therapeutic use MH - PPAR delta/metabolism MH - PPAR-beta/metabolism MH - Parkinson Disease/complications/*drug therapy/metabolism/pathology MH - Pars Compacta/drug effects/metabolism/pathology MH - Protein Serine-Threonine Kinases/metabolism MH - Rats MH - Rotenone/*pharmacology MH - Signal Transduction/*drug effects MH - TNF Receptor-Associated Factor 2/metabolism MH - Telmisartan OTO - NOTNLM OT - Apoptosis OT - Inositol-requiring enzyme 1alpha OT - Parkinson's disease OT - Peroxisome proliferator-activated receptor-beta/delta OT - Telmisartan EDAT- 2016/02/18 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/02/17 06:00 PHST- 2015/08/31 00:00 [received] PHST- 2016/02/10 00:00 [revised] PHST- 2016/02/11 00:00 [accepted] PHST- 2016/02/17 06:00 [entrez] PHST- 2016/02/18 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S0014-2999(16)30064-4 [pii] AID - 10.1016/j.ejphar.2016.02.042 [doi] PST - ppublish SO - Eur J Pharmacol. 2016 Apr 5;776:106-15. doi: 10.1016/j.ejphar.2016.02.042. Epub 2016 Feb 12.