Update on the pathological roles of prostaglandin E in neurodegeneration in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E (PGE) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.