Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection

Abstract

Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) for treating cyclooxygenase-2 (COX-2 or PTGS2)-governed pathological conditions. Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects including neuroprotection in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP/PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP/Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies targeting this key inflammatory prostaglandin receptor.

Radiation-induced PGE2sustains human glioma cell growth and survival through EGF signaling

“…However, the number of colonies in the co-cultures (primary cultures + irradiated U251 cells) was significantly increased. Next, we examined the expression of the different PGE 2 receptors in the primary cultures: first the expression of EP2 as it is the most widely expressed prostaglandin receptor in the brain and it is functionally coupled to anti-apoptotic and protective functions in neurons and in secondary neurotoxicity during inflammation [18, 19]. …”

Inflammation in Epileptic Encephalopathies

“…The role of the cytokines in the processes linked with epileptogenesis can be complex, including a possible protective or compensatory role. Dual effects of neuroinflammatory pathways have been demonstrated with cyclooxygenase-2 (COX-2) inhibitors in post-status epilepticus injury, depending upon the context they are applied into (Jiang & Dingledine 2013). As an example, increased production of the pro-inflammatory cytokines can increase production of anti-inflammatory cytokines, such as IL-10.…”

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

“…Further, major deleterious effects associated with induction of inflammatory mediators after SE (i.e., neuronal injury, inflammatory cytokine burst, leakage of BBB) appear to involve the activation of IL-1 receptor type 1 (IL-1R1 for IL-1β), Toll-like receptor 4 and Receptor for Advanced Glycation End product (TLR4 and RAGE for HMGB1) and EP2 receptors (for PGE2) [74,82,87–89], pointing to these signaling pathways as major inflammatory mediators in the brain following SE. In addition, the extravasation of albumin into the hippocampus and cortex, normally observed several hours to days after SE [59,75,84] and indicative of breach of the BBB, was abolished in both the conditional COX-2 knockout and in wild-type mice treated with the EP2 antagonist [84,86] as well as by IL-1 receptor antagonist (IL-1ra, anakinra) [87,89], indicating a key role for the IL-1β/IL-1R1 and COX-2/EP2 system in controlling the BBB integrity after SE.…”