Abstract TP114: Modulation of Blood Accumulation and Angiogenic Responses by PGE2-EP3 Signaling After ICH in Aged Mice

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Abstract

With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs is expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, whom display increased mortality and worse functional outcomes compared to 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. PGE2 levels are dramatically upregulated following brain injury and have been shown to modulate the deleterious excitotoxic and neuroinflammatory processes resulting from activation of glial cells and infiltration of blood cells and proinflammatory molecules through its four EP receptors, EP1-4. 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=0.0336) and improves neurological functional recovery, as identified by lower neurological deficit scores at 48h (p=0.0013) and 72h (p=0.0063), and increased gross (p=0.0038) and fine motor (p=0.0556) movements and decreased resting time (p = 0.0280) at 72h. Immunohistological staining was performed to investigate possible mechanisms of EP3-mediated neurotoxicity. Identified mechanisms include reduced blood accumulation (p=0.0277) and modulation of angiogenic and astroglial responses, where EP3-/- mice have increased striatal astrogliosis (p=0.0498) and VEGF immunoreactivity (p=0.0115), and tended to have increased cortical astrogliosis (p=0.1874). 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.

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