Oxyresveratrol mitigates cellular toxicity in an in-vitro and in-vivo model of Parkinson's disease

Abstract

Aims: The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been greatly demonstrated as a pathological phenomenon in Parkinson’s disease (PD). These signalling mechanisms are activated when there is an increased burden of misfolded proteins in neurons, primarily alpha synuclein, in the case of PD. In this study we aim to elucidate the effects of oxyresveratrol, a potent antioxidant, on the UPR in PD. Furthermore, the neuro-protective potential of oxyresveratrol in an in-vivo model was tested. Method: The murine dopaminergic Mes 23.5 cell line was treated with the parkinsonian mimetic 6-hydroxydopamine (6-OHDA). Effects of oxyresveratrol on the downstream effectors mediating the UPR were investigated by immunoblotting and quantitative PCR. For the in-vivo model, male Sprague-Dawley rats were injected stereotactically with 6-OHDA. Subsequently, immunohistochemistry to study midbrain pathology and behaviour tests to assess motor debilitation, were performed. Results: Oxyresveratrol reduced the expression of ATF4 and CHOP, following induction of ER stress in the Mes 23.5 cells by 6-OHDA. The activation of this branch of the UPR, downstream of PERK, propels the cell towards apoptosis. Motor dysfunction was also alleviated in the oxyresveratrol-treated rats, along with a partial preservation of dopaminergic cells in the substantia nigra pars compacta. Conclusion: This study suggests that attenuation of apoptosis driven by the UPR may be an important mechanism of action of oxyresveratrol. Moreover, a protection of motor function and cell loss seen in the in vivo model suggests that oxyresveratrol may be a useful therapeutic candidate for PD.