PGE₂-EP3 signaling exacerbates intracerebral hemorrhage outcomes in 24-mo-old mice

Abstract

With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs are expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, who display increased mortality and worse functional outcomes compared with younger patients. This study aimed to investigate the contribution of the prostaglandin E2 (PGE2) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2-EP3 axis exacerbates ICH outcomes in young mice. Here, we show that EP3 receptor deletion results in 17.9 ± 6.1% less ICH-induced brain injury (P < 0.05) and improves neurological functional recovery (P < 0.01), as identified by lower neurological deficit scores, decreased resting time, and more gross and fine motor movements. Immunohistological staining was performed to investigate possible mechanisms of EP3-mediated neurotoxicity. Identified mechanisms include reduced blood accumulation and modulation of angiogenic and astroglial responses. Using this aged cohort of mice, we have confirmed and extended our previous results in young mice demonstrating the deleterious role of the PGE2-EP3 signaling axis in modulating brain injury and functional recovery after ICH, further supporting the notion of the EP3 receptor as a putative therapeutic avenue for the treatment of ICH.

PGE2‐EP3 signaling exacerbates hippocampus‐dependent cognitive impairment after laparotomy by reducing expression levels of hippocampal synaptic plasticity‐related proteins in aged mice

“…20,46 Previous studies have confirmed PGE2-EP3 signaling axis in modulating multiple forms of brain disorders, including ischemic and hemorrhagic stroke, and Alzheimer's diseases, using EP3 knockout mice. [47][48][49] In this study, we found that it is the EP3 receptor that dramatically upregulated at both transcription and translation levels after mice received laparotomy, especially in neu- In our study, we also observed that CREB, Arc, and BDNF dramatically decreased after laparotomy in mice. That means the synaptic plasticity mechanism is possibly involved in the development of POCD.…”

“…EP3 signaling in response to PGE2 is primarily coupled to Gi protein, which reduces cAMP formation, and therefore termed the “inhibitory” receptor . Previous studies have confirmed PGE2‐EP3 signaling axis in modulating multiple forms of brain disorders, including ischemic and hemorrhagic stroke, and Alzheimer's diseases, using EP3 knockout mice . In this study, we found that it is the EP3 receptor that dramatically upregulated at both transcription and translation levels after mice received laparotomy, especially in neurons, but not other EP receptors (EP1, EP2, and EP4), which may imply the direct influence of EP3 receptors on neuronal function.…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…EP3 receptor is the most abundant receptor in brain (Leclerc et al, 2016) and appears to play an important role in acute ischemic stroke. A study showed that activation of EP3 receptor with ONO-AE-248 increased infarct size in experimental stroke (Ahmad et al, 2007).…”

A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

“…The main models discussed in this section represent major risk factors for ICH in patients: hypertension, cerebral amyloid angiopathy (CAA) and cerebral small vessel disease (CSVD). The HEADS committee also highlighted the need to develop models of modifiable and non-modifiable risk factors, such as alcoholism and ageing to further understand how ICH can be prevented in these populations, as there are relatively few papers which utilise these risk factors [20,[56][57][58][59][60][61][62][63].…”