Abstract

Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I2 (PGI2). The present study investigated whether the PGI2 IP receptor plays an important role in brain injury after global cerebral ischemia in aged mice. Adult young (2–3 months) and aged (12–15 months) male C57Bl/6 wild-type (WT) or IP receptor knockout (IP KO) mice underwent a 12 min bilateral common carotid artery occlusion (BCCAO) or a sham surgery. Behavior tests (neurologic deficit and T-maze) were performed 3 and 7 days after BCCAO. After seven days of reperfusion, the numbers of cells positive for markers of neurons, astrocytes, microglia, myeloperoxidase (MPO) and phosphorylated CREB (p-CREB) were evaluated immunohistochemically. Interestingly, in young and aged IP KO ischemic mice, there was a significant increase (p < 0.01) in cognitive deficit, hippocampal CA1 pyramidal neuron death, microglia and MPO activation, while p-CREB was reduced as compared to their corresponding WT controls. These data suggest that following ischemia, IP receptor deletion contributes to memory and cognitive deficits regulated by the CREB pathway and that treatment with IP receptor agonists could be a useful target to prevent harmful consequences.

Highlights

  • Transient global cerebral ischemia, arising in humans, can be an aftermath of cardiac arrest or severe systemic hypotension

  • These data suggest that following ischemia, IP receptor deletion contributes to memory and cognitive deficits regulated by the CREB pathway and that treatment with IP receptor agonists could be a useful target to prevent harmful consequences

  • Our findings suggest that transient global cerebral ischemia mediates CREB phosphorylation and genetic deletion of Prostaglandin I2 (PGI2) IP receptor decreases pCREB, which act as a molecular marker of memory processing in the hippocampus for cognitive function [14,35,36]

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Summary

Introduction

Transient global cerebral ischemia, arising in humans, can be an aftermath of cardiac arrest or severe systemic hypotension. It leads to major neuropsychological dysfunctions, including learning and memory disabilities especially in aged populations [1,2]. One needs to take into account intracellular calcium (Ca2+) overload, the toxic effects of excitatory amino acids, an aberrant increase in oxygen free radicals, the activation of inflammatory factors and death gene regulation [4]. COX-2 is highly inducible by inflammatory stimuli and increases the production of five prostanoids: prostaglandin PGE2, (PG) D2, PGF2α, PGI2, and thromboxane A2 [6]

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