Prostaglandin J2 reduces catechol-O-methyltransferase activity and enhances dopamine toxicity in neuronal cells.

There is clear evidence that an inflammatory reaction is mounted within the CNS following trauma, stroke, infection and seizures, thus augmenting brain damage. Furthermore, chronic inflammation of the CNS is implicated in many neurodegenerative disorders. However, the effects of products of inflammation on neuronal cells are poorly understood. Herein, we characterize the effects of a neurotoxic product of inflammation, prostaglandin J2 (PGJ2), on catechol-O-methyltransferase (COMT) in human dopaminergic-like neuroblastoma SK-N-SH cells and rat (P2) cortical neurons. COMT metabolizes catechols and catecholamines, a pathway relevant to neurodegeneration. PGJ2 treatment reduced the expression and activity of COMT, induced its sequestration into perinuclear aggregates and potentiated dopamine toxicity. The large COMT aggregates were co-localized with the centrosome, suggesting an aggresome-like structure. Our results indicate that COMT impairment induced by PGJ2 treatment may increase the concentration of dopamine (or its metabolites) to neurotoxic levels. Thus, COMT impairment following pro-inflammatory events may be a potential risk factor in neurodegeneration.