Journal
MOLECULAR NEUROBIOLOGY
Volume 53, Issue 6, Pages 3822-3831Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-015-9309-9
Keywords
Parkinson's disease; PPAR beta/delta; ER stress; Neuroprotection
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Funding
- National Natural Science of China [81271418]
- Natural Science Foundation of Jiangsu Province [BK201254]
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Two recent studies demonstrated that peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) 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 PPAR beta/delta 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 1 alpha (IRE1 alpha) 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 IRE1 alpha-caspase-12-mediated ER stress pathway may represent one potential mechanism underlying the neuroprotective effects of PPAR beta/delta agonist in the rotenone rat model of PD.
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