Inhibition of endoplasmic reticulum stress-activated IRE1 alpha-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rat model of Parkinson's disease

摘要

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 1 alpha (IRE1 alpha) is necessary and sufficient to trigger ER stress. In the present study, we aimed to determine whether ER stress-activated IRE1 alpha-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 IRE1 alpha, 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 IRE1 alpha-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 IRE1 alpha-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rats of PD. (C) 2016 Elsevier B.V. All rights reserved.