title: PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α-Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson's Disease.
abstract: Two recent studies demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonists exerted neuroprotective effects in mouse model of Parkinson's disease (PD). However, the underlying mechanisms remain unknown. Endoplasmic reticulum (ER) stress plays a major role in rotenone-induced dopaminergic neuronal degeneration. In the present study, we explored whether GW501516, a selective and high-affinity PPARβ/δ agonist, could protect the dopaminergic neurons against degeneration and improve PD behavior via suppressing the ER stress in the rotenone rat model of PD. GW501516 was administered intracerebroventricular infusion. Catalepsy and open field tests were used to test catalepsy and locomotor activities. The levels of dopamine and its metabolites were determined using high-performance liquid chromatography. Western blot and immunohistochemistry analysis were performed to assess dopaminergic neuronal degeneration. Quantitative real-time RT-PCR and Western blot analysis were executed to detect ER stress. TUNEL and immunohistochemistry assays were used to detect ER stress-mediated apoptosis. Our results showed that GW501516 ameliorated the catalepsy symptom and increased locomotor activity. Meanwhile, GW501516 partially reversed the loss of dopaminergic neurons. Moreover, GW501516 suppressed the activation of ER stress markers including inositol-requiring enzyme 1α (IRE1α) and caspase-12. Furthermore, GW501516 inhibited caspase-12-mediated neuronal apoptosis. These findings suggest that GW501516 conferred neuroprotection of not only biochemical and pathological attenuation but also behavioral improvement in the rotenone rat model of PD. More importantly, we demonstrated for the first time that suppressing IRE1α-caspase-12-mediated ER stress pathway may represent one potential mechanism underlying the neuroprotective effects of PPARβ/δ agonist in the rotenone rat model 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, People's Republic of 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, People's Republic of 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, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Ou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing Medical University, P.O. Box 211166, No. 818 Tianyuan East Road, Jiangning District, Nanjing, People's Republic of China.
authors.forename: Dongya
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, P.O. Box 210006, No. 68 Changle Road, Nanjing, People's Republic of China. zhangyingdong@aliyun.com.
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12 / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009097:Multienzyme Complexes / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000066829:Neuroprotection / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012402:Rotenone; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: C575026:Ern1 protein, rat; C425931:GW 501516; D009097:Multienzyme Complexes; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; D012402:Rotenone; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D053454:Caspase 12; D004298:Dopamine
keywords: ER stress; Neuroprotection; PPARβ/δ; Parkinson’s disease