Abstract
Beraprost sodium is a new stable, orally active Prostaglandin I2 analogue. The aim of this study was to determine the effect of beraprost on cognitive dysfunction and locomotor impairment induced by bilateral common carotid artery occlusion in mice. We investigated the ameliorating effect of beraprost through PGI2 IP receptor by studying neurologic deficit assessment and T-maze testing in young and old male C57Bl/6 wild-type (WT) and IP receptor knockout (IP KO) mice following a 12 min bilateral common carotid artery occlusion (BCCAo) and 7 days of reperfusion. Beraprost reversed BCCAo induced cognitive impairment and neurological deficit in a dose dependent manner. Immunohistochemical studies showed attenuation of neuronal cell death, astrogliosis, microglial invasion, and myeloperoxidase (MPO) activity in both young and old WT mice after post treatment with beraprost. Moreover, after BCCAo, phosphorylated cAMP response element binding protein positive cell numbers were increased with beraprost treatment over vehicle treated controls. These results show that beraprost treatment attenuated cognitive dysfunction and neurological deficits induced by BCCAo, and suggest that this effect may be mediated by the neuroprotective effects of treatment.
Highlights
Transient global cerebral ischemia remains a leading cause of death or deterioration in the quality of life in aging animals and humans [1,2]
The present study demonstrates that post treatment of mice with beraprost following transient global cerebral ischemia induced by bilateral common carotid artery occlusion (BCCAo) markedly ameliorated hippocampal injuries as evaluated immunohistochemically and behaviorally
This suggests that the PGI2 agonist beraprost, acting through the IP receptor, attenuates the cognitive functional impairments caused by BCCAo by sparing neuronal loss in the hippocampal CA1 region
Summary
Transient global cerebral ischemia remains a leading cause of death or deterioration in the quality of life in aging animals and humans [1,2]. Previous reports suggest that cyclooxygenase 2 (COX-2) plays a critical role in hippocampal CA1 injury after global cerebral ischemia [7]. Different prostaglandins such as prostaglandin (PG) E2, PG D2, PGF2α, PGI2, and thromboxane A 2 mediate COX-2 effects mainly through G-protein-coupled receptors, i.e., PGE2 EP (1–4), PGD2 DP (1–2), PGF2α FP, PGI2 IP and TXA2 TP receptors. Each of these receptors mediates different effects EP2, EP4, DP1 and IP receptor through an increase in cyclic AMP (cAMP) levels and EP1, FP, TP cause increase in Ca2+ mediated toxicity [8]
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