COX-2 on the brain

Despite intensive research efforts, the pathogenic events underlying Parkinson's disease (PD), which is characterized by the loss of nigrostriatal dopaminergic neurons, remain elusive. There are, however, a number of clues, one of which has emerged from epidemiological studies indicating a link between inflammation and a number of neurodegenerative diseases. In support of this link, elevated levels of the inflammation-associated enzyme cyclooxygenase-2 (COX-2) — and those of its product, prostaglandin E₂ (PGE₂) — have been implicated in neurodegeneration.

Following this lead, Przedborksi and colleagues, reporting in the 29 April issue of the Proceedings of the National Academy of Sciences, have asked whether, and how, COX-2 levels contribute to PD. The group found that in post-mortem PD specimens COX-2 expression was induced specifically within substantia nigra pars compacta (SNpc) dopaminergic neurons. The same was found in mice treated with 2-methyl 1-4-phenyl-1,2,3,6-tertrahydropyridine (MPTP), a chemical commonly used to model the loss of nigrostriatal dopaminergic neurons seen in PD.

So what leads to elevated COX-2 levels, and how do these contribute to PD? Teismann et al. found that COX-2 induction after MPTP administration is mediated through a JUN N-terminal kinase/c-JUN-dependent pathway, and further that neurodegeneration could be reduced by COX-2 inhibitors. Moreover, it was shown that the catalytic activity of COX-2 is crucial to the neurodegenerative process in SNpc dopaminergic neurons in the MPTP model, and by extension probably in PD also. By contrast, the inhibition of COX-1 provided no protective effects against MPTP. Two possible explanations for the effects of COX-2 were proposed. Neurons overexpressing COX-2 could cause their own death, by synthesizing excess amounts of PGE₂ that result in the production of micro-glial-derived mediators, which then aid the killing of the neurons. Alternatively, COX-2 could cause cell death in a cell-autonomous manner through the production of reactive oxygen species generated by the catalytic activity of COX-2, which in turn can result in oxidants such as dopamine-quinone. The authors suggest that the neuroprotective effect of COX-2 inhibition could result from mitigating the oxidative damage caused by dopamine-quinone, which has previously been implicated in PD. These results are obviously of relevance to the further investigation of targets for PD therapeutics.