The Role of mPGES-1 in Inflammatory Brain Diseases

Abstract

Prostaglandin E₂ (PGE₂) has been thought to be an important mediator of inflammation in peripheral tissues, but recent studies clearly show the involvement of PGE₂ in inflammatory brain diseases. In some animal models of brain disease, the genetic disruption and chemical inhibition of cyclooxygenase (COX)-2 resulted in the reduction of PGE₂ and amelioration of symptoms, and it had been thought that PGE₂ produced by COX-2 may be involved in the progression of injuries. However, COX-2 produces not only PGE₂, but also some other prostanoids, and thus the protective effects of COX-2 inhibition, as well as severe side effects, may be caused by the inhibition of prostanoids other than PGE₂. Therefore, to elucidate the role of PGE₂, studies of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE₂ synthesis, have recently been an active area of research. Studies from mPGES-1 deficient mice provide compelling evidence for its role in a variety of inflammatory brain diseases, such as ischemic stroke, Alzheimer’s disease and epilepsy, and clues for developing new therapeutic treatments for brain diseases by targeting mPGES-1. Considering that COX inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological functioning of the brain and peripheral tissues, as well as induce gastro-intestinal, renal and cardiovascular complications, mPGES-1 inhibitors are expected to be injury-selective and have fewer side-effects when treating human brain diseases. Thus, this paper focuses on recent studies that have demonstrated the involvement of mPGES-1 in pathological brain diseases.

Graphical Abstract