Abstract
Activation of the prostacyclin (PGI2) IP receptor is protective in brain ischemia. However, there is very limited information of the molecular mechanisms of protection and the feasibility to target this pathway in stroke. MRE-269, a highly selective PGI2/IP receptor agonist, has been recently discovered. This IP agonist has a long half-life in vivo and is currently in phase III clinical trials for pulmonary hypertension. We hypothesized that post-ischemic treatment with MRE-269 provides neuroprotection in a rat ischemic stroke model. Young male rats (3-4-month old) were subjected to middle cerebral artery occlusion (MCAO) for 90 min and treated intravenously with either vehicle (n=14) or MRE-269 (0.1, 0.25, 0.5, and 1 mg/kg, n=10-14/group) at the start of reperfusion. At 48 h post-MCAO, rats were sacrificed to determine infarct size, blood-brain barrier (BBB) damage (IgG extravasation), hemorrhagic transformation (brain hemoglobin levels), and matrix metalloproteinase (MMP)-9 activity. In a separate experiment, aged male rats (18-20-month old) underwent 90 min of MCAO and randomly selected to receive intravenously either vehicle (n=11) or MRE-269 (0.25 mg/kg, n=11) starting at 4.5 h post-MCAO. Additional doses were given every 12 h for the first 48 h, and then one injection daily for 7 days post-MCAO. The accelerating rotarod and the adhesive removal tests were conducted before and at 3, 7, 14 and 21 days after MCAO by an investigator blinded to treatment groups. Infarct volume was quantified by MRI at 48 h and 21 days post-MCAO. In young rats, MRE-269 dose-dependently reduced cortical infarct size. MRE-269-treated rats (0.25 mg/kg) had significantly reduced BBB damage and less hemorrhagic transformation. Compared with the vehicle group, MRE-269-treated animals showed a significant reduction in brain MMP-9 activity. In aged rats, MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions following MCAO. Quantitative MRI data showed that MRE-269 significantly reduced infarct volume compared with vehicle-treated rats. Our data suggest that targeting the PGI2/IP receptor with MRE-269 is a novel strategy to reduce neurovascular injury and promote long-term neurological recovery in ischemic stroke.
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