Study On The Protective Effect And Mechanisms Of PPARβ/δ Activation In Parkinson’s Disease

Parkinson’s disease (PD) is a chronic neurodegenerative disease, which is clinically characteristic of the movement disorder and seriously affects the quality of life of patients with clinical characteristic of the movement disorders and the bad quality of life. PD is common in the elderly and the prevalence in the elderly population increases with age, which has become a major disease affecting the health of the elderly along with the process of aging in our country. So far, the etiology and pathogenesis of PD has not been fully clarified. In addition, the current clinical treatment of drugs can only control symptoms and can not delay the progress of the disease. Therefore, it is urgent to clarify the pathogenesis of PD, screen the potential pharmacological intervention targets and develop better anti PD drugs.Recent studies demonstrated that peroxisome proliferator-activated receptor (3/5 (PPARβ/δ) agonists exerted neuroprotective effects in mouse model of PD. However, the underlying mechanisms remain unknown. Endoplasmic reticulum(ER) stress plays a major role in rotenone-induced dopaminergic neuronal degeneration. Additionally, studies have revealed that inositol-requiringenzyme (IREla) is necessary and sufficient to trigger ER stress. In the first part of our 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 blotting and immunohistochemistry analysis were performed to assess dopaminergic neuronal degeneration. Quantitative real-time RT-PCR and western blotting analysis were executed to detect ER stress. TUNEL and immunohistochemistry assay 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-requiringenzyme1α (IREla) and caspases-12. Furthermore, GW501516 inhibited caspases-12-mediated neuronal apoptosis. These findings suggest that GW501516 confered 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.Telmisartan, one unique angiotensin Ⅱ (Ang Ⅱ) type 1 receptor (AT1R) blocker (ARB), has been attracting attention due to its putative peroxisome proliferator-activated receptor (PPAR)-γ or β/δ actions. Recently, studies have shown that telmisartan confers neuroprotection in the mouse MPTP model of PD. However, the underlying mechanisms have not been fully clarified. Recently, accumulating evidence has shown that ER stress plays a crucial role in rotenone-induced neuronal apoptosis. Additionally, studies have revealed that IRE1α is necessary and sufficient to trigger ER stress. In the second part of our 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), caspases-12 and PPAR-β/δ was detected by western blotting. Neuronal apoptosis was assessed by TUNEL and immunohistochemistry. Our results show that telmisartan ameliorated the catalepsy symptom and attenuated dopamine depletion as well as a-synuclein accumulation. Moreover, telmisartan decreased ER stress-mediated neuronal apoptosis. Furthermore, telmisartan inhibited IRE1α-TRAF2-caspase-12 apoptotic signalling 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.