PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease

Abstract

Stroke and Alzheimer’s disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E2 EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult that observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared to wildtype mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. Aβ-induced toxicity (18.0 ± 7.1%) and Ca2+ response (91.8 ± 12.9%) were also reduced in EP1−/− neurons compared to control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with COX-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

“…In addition, early-stage AD is characterized by increased cerebrospinal fluid levels of PGE 2 (19,20), supporting the hypothesis that inflammatory actions of brain COX/PGE 2 may underlie preclinical development of AD. Consistently, studies in AD model mice demonstrate reduced amyloid pathology with global deletion of individual PGE 2 G protein-coupled receptors (21)(22)(23), and additional studies have shown a suppressive signaling effect of the PGE 2 receptor EP2 on Aβ 42 phagocytosis (24,25). These studies, along with the recent demonstration of a broad regulatory function of EP2 signaling on cell cycle, cytoskeletal, and immune genes in quiescent microglia (26), suggest that microglial EP2 signaling may be a general suppressor of immune and nonimmune processes that protect against onset and progression of AD pathology.…”

Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

“…Moreover, using a mouse model of cerebral ischemia and Alzheimer’s disease, we have shown that EP1 receptor blockade could be beneficial for treatment of both conditions [33]. In addition, recent data from another group indicate that the EP1 receptor antagonist used in our study demonstrated strong a therapeutic effect of repeated treatments with SC-51089 (40 µg/kg) in a murine model of Huntington’s disease and pointed out this compound as a new therapeutic candidate for motor and cognitive deficits characteristic for this and other neurodegenerative disorders [40].…”

“…Because of encouraging results from preclinical studies from various teams, including ours, effort have been made to investigate the effects of EP1 receptor inhibitors in preclinical models of several other neurological and neurodegenerative conditions, including epilepsy [38], [39], acute surgical brain injury [25], hemorrhagic stroke [24], and Huntington [40] and Alzheimer’s [33] diseases. However, our recent mouse study indicates that the EP1 receptor would be involved in neuroprotective pathways following ICH [24], suggesting that the role of the EP1 receptor in brain injuries is complex.…”

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

“…Over the past decade, studies have demonstrated that genetic ablation or pharmacological inhibition of G αq -coupled EP1 receptor is neuroprotective following experimental ischemic injuries [45–48]. These results from ischemia models suggest that the EP1 receptor might contribute to PGE 2 -mediated neurotoxicity.…”