ROLE OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 IN MOUSE MODELS OF STRESS

Abstract Although there are many antidepressants available, most of which are drugs based on the monoamine hypothesis, and about one third of patients experience treatment-resistant depression. Thus, new therapeutic targets for antidepressants need to be discovered. We have previously reported that microsomal prostaglandin E synthase-1 (mPGES-1), a terminal inducible enzyme for PGE2 synthesis, induced at lesion sites in animal models and patients with Parkinson's disease and cerebral infarction contributes to the brain inflammation and deterioration of the pathology through PGE2 production1,2). Recently, brain inflammation has been reported to be involved in not only stroke or neurodegenerative diseases, but also psychiatric disorders. In this study, to elucidate the contribution of mPGES-1 to stress-induced brain inflammation and functions, we used two mouse models of stress, acute restraint stress (RS: 6 h) and social defeat stress (SDS). mPGES-1 mRNA was significantly increased after RS. Induction of mPGES-1 protein was observed in neurons in the frontal cortex (FC). PGE2 in FC was also significantly upregulated in wild-type (WT) mice, but not in mPGES-1 knockout (ES1KO) mice. The inflammatory responses, such as increases in GFAP and TNF-α, observed after RS in ES1KO were significantly less than those in WT. In sucrose preference test (SPT), the ratio of sucrose intake after RS in WT was significantly less than that in ES1KO. In SDS model, upregulation of mPGES-1 mRNA was also observed in FC, amygdala and ventral tegmental area at Day1 and 4. Induction of mPGES-1 protein was observed in neurons in the FC at Day4. PGE2 in FC was significantly upregulated at Day4 in WT mice, but not in ES1KO mice. The inflammatory responses, such as increases in Iba-1, GFAP and IL-1β, observed at Day10 of SDS in ES1KO were significantly less than those in WT. The ratio of sucrose intake at Day8 of SDS in WT was significantly less than that in ES1KO. Taken together, these results suggest that mPGES- 1 is induced by both RS and SDS stress in FC neurons, and then contributes to brain inflammation and anhedonia through PGE2 production. Thus, mPGSE-1 may be a promising novel therapeutic target for treatment of depression. References 1)Ikeda-Matsuo Y, et al., Proc Natl Acad Sci U S A. 2006; 103(31): 11790-11795. 2)Ikeda-Matsuo Y, et al., Neurobiol Dis. 2019;124: 81-92.