MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress

Abstract

Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson’s disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone. In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in primary ventral mesencephalic (VM) neurons, an in vitro model of PD, and if so, whether the protective effects of COX-2 inhibitors on dopamine mediated MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis result from the reduction of ROS. Reserpine, a dopamine-depleting agent, significantly reduced VM neurotoxicity induced by MPP+, whereas dopamine had an additive effect on MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis. However, inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP+-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons. These results suggest that dopamine itself mediates MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2.

Cyclooxygenase‐2 Regulates NLRP3 Inflammasome‐Derived IL‐1β Production

“…ROS play an important role in NLRP3 inflammasome activation (Tschopp and Schroder, ; Bauernfeind et al, ). Because COX‐2 is able to generate ROS (Fraser, ; Hsieh et al, ), we investigated whether COX‐2 regulates ROS production in response to LPS and ATP stimulation. We found that LPS‐induced ROS production was not affected by the COX‐2 inhibitor (Fig.…”

“…ROS not only plays an important role in the priming step of NLRP3 inflammasome, but also regulates the activation step of the NLRP3 inflammasome (Tschopp and Schroder, ). The induction of COX‐2 expression leads to PGE 2 production and is usually accompanied by an increase in ROS levels (Fraser, ; Hsieh et al, ). Conversely, the inhibition of COX‐2 decreases ROS generation in human promonocytic cells infected by C. pneumonia (Mouithys‐Mickalad et al, ) and in myeloid‐derived suppressor cells and macrophages from tumor‐bearing mice (Veltman et al, ).…”

A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease

“…Mesencephalic dissociated neurons were prepared from the ventral mesencephalon of E14 rat (Sprague–Dawley) foetus as previously (Hsieh et al, 2011). Experimental protocols were in accordance with Home Office and institutional guidelines.…”

“…The apoptosis assay was performed as described before (Hsieh et al, 2011). Apoptosis was detected by Hoechst 33258 staining (Molecular Probes).…”

Neuroimmunological Processes in Parkinson's Disease and their Relation to α-Synuclein: Microglia as the Referee between Neuronal Processes and Peripheral Immunity

“…More specific blockade of inflammation has been achieved successfully with inhibitors of COX-2 (Sanchez-Pernaute et al, 2004), which has been shown to be increased in PD SN (Teismann et al, 2003). COX-2 can induce DA oxidation and NFκB-induced inflammatory responses in microglia (Schwieler et al, 2006; Hsieh et al, 2011); additionally it induces prostaglandin production that triggers the peripheral immune system (Font-Nieves et al, 2012). …”