Neuroprotective properties of prostaglandin I2 IP receptor in focal cerebral ischemia

Abstract

We and others have identified that inhibition of cyclooxygenase might not be the optimal approach to limiting brain damage after stroke. Now we are investigating the unique properties of the various prostaglandin receptors to determine whether blocking those that mediate toxicity or stimulating those that reduce toxicity will improve neurological outcomes. Here, we determined the respective contribution of the prostaglandin I2 (PGI2) receptor in transient middle cerebral artery (MCA) occlusion (tMCAO) and permanent MCAO (pMCAO) preclinical stroke models by using male wildtype (WT) and IP receptor knockout (IP−/−) C57Bl/6 mice. In addition, we investigated the putative preventive and therapeutic effects of the IP receptor agonist beraprost. The infarct volumes and neurological deficit scores (NDS) were significantly greater in IP−/− than in WT mice after both tMCAO and pMCAO. Interestingly, beraprost pretreatment (50 or 100 μg/kg p.o.) 30 min before tMCAO and post-treatment (100 μg/kg p.o.) at 2 or 4.5 h of reperfusion significantly reduced the neurological deficit score and infarct volume in WT mice. Post-treatment with beraprost (100 μg/kg p.o.) 4.5 h after pMCAO also significantly decreased neurological deficits and infarct volume in WT mice. Together, these novel findings suggest for the first time that PGI2 IP receptor activation can attenuate anatomical and functional damage following ischemic stroke.

HO1 and Wnt expression is independently regulated in female mice brains following permanent ischemic brain injury

“…It has also been reported that HO1 −/− and WT male mice show no differences in brain infarct volume in the tMCAO reperfusion model (Dore et al, 1999) of 1 h occlusion and 23 hr reperfusion whereas in pMCAO model it was demonstrated that after 7 days of ischemia, HO1 −/− male animals had significantly higher infarct volume as compared to WT male animals, suggesting a neuroprotective role of HO1(Shah et al, 2011). HO1 neuroprotective properties were also observed in NMDA-induced neurotoxicity model (Saleem et al, 2010) and after ischemic preconditioning, where male HO1 −/− mice did not shown any protection and suffered from higher brain damage as compared to WT after 48 hrs of permanent ischemia (Zeynalov et al, 2009). We recently reported that HO1 −/− male mice showed lower neurogenesis as compared to WT animals following permanent ischemia (Nada et al, 2014).…”

Intravenous Treatment With Coenzyme Q10 Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Brain Ischemia in Rats

“…13 The sizes of brain lesions in the saline group were consistent with those obtained by other researchers (25%-28% of ipsilateral hemisphere), demonstrating the reproducibility of focal ischemia induction. 14,15 Between 1980 and 2000 there were a few studies showing the effectiveness of CoQ10 in different animal models of brain damage. [16][17][18] However, most research used preventive administration of a large dose of CoQ10, and/ or its enteral administration.…”

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

“…In addition, beraprost reduces the neurological deficit score and infarct volume after both transient and permanent middle cerebral artery occlusion in an adult mouse model. In these animal models of brain ischemia, PGI 2 probably protects neurons by enhancing intracellular cAMP production and reducing Ca 2ϩ overload in neurons to mitigate subsequent neuronal cell death (Saleem et al, 2010). Studies have also examined the potential IP receptor involved in the actions of PGI 2 after brain ischemia.…”