ドパミン神経でのPGE<sub>2</sub>合成酵素誘導はパーキンソン病での神経変性に寄与する

Although increased production of prostaglandin E2 (PGE2) has been implicated in tissue damage in several pathological settings, the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, in dopaminergic neurodegeneration remains unclear. Here we show that mPGES-1 is up-regulated in the dopaminergic neurons of the substantia nigra of postmortem brain tissue from PD patients and in 6-hydroxydopamine (6-OHDA)-induced PD mice. The expression of mPGES-1 was also up-regulated in cultured dopaminergic neurons stimulated with 6-OHDA. The genetic deletion of mPGES-1 not only abolished 6-OHDA-induced PGE2 production but also attenuated 6-OHDA-induced dopaminergic neurodegeneration both in vitro and in vivo, while it did not affect the productions of PGI2, PGD2 and TXA2. Nigrostriatal projections, striatal dopamine content, and neurological functions were significantly impaired by 6-OHDA administration in wild-type mice, but not in mPGES-1 knockout mice. These results suggest that induction of mPGES-1 in dopaminergic neurons enhances 6-OHDA-induced dopaminergic neurodegeneration through excessive PGE2 production. Thus, mPGES-1 may be a valuable therapeutic target for treatment of PD