Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.
Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog.
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DOI：
10.1161/strokeaha.117.016474
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发表时间：
2017-07
期刊：
影响因子：
8.3
通讯作者：
Candelario-Jalil E
中科院分区：
文献类型：
--
作者：
Yang C;DeMars KM;Alexander JC;Febo M;Candelario-Jalil E
Targeting the prostacyclin/IP receptor to reduce stroke injury has been hindered by the lack of selective drugs. MRE-269 is the active metabolite of selexipag showing a very high selectivity toward the IP receptor. Selexipag has been recently approved for clinical use in pulmonary hypertension. We hypothesized that post-ischemic treatment with MRE-269 provides long-lasting neuroprotection with improved neurological outcomes in a clinically relevant rat stroke model. Aged male Sprague-Dawley rats underwent transient middle cerebral artery occlusion (MCAO) and were randomly selected to receive either vehicle or MRE-269 (0.25 mg/kg) intravenously starting at 4.5h post-ischemia. Accelerating rotarod and adhesive removal tests were conducted before and at 3, 7, 14 and 21 days after stroke. Infarct volume was quantified by MRI at 48h and 21 days post-MCAO. In parallel experiments, cerebral cortex samples from stroke and non-stroke sides from vehicle- and MRE-269-treated groups were collected at 18h post-MCAO for molecular biology analyses. Quantitative MRI data showed that post-ischemic MRE-269 treatment significantly reduced infarct volume compared with vehicle-treated rats at both 48 h and three weeks after stroke. MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions following MCAO, which was associated with a reduced weight loss in animals receiving the IP receptor agonist. Post-ischemic MRE-269 treatment reduced pro-inflammatory cytokines/chemokines and oxidative stress. Damage to the blood-brain barrier, as assessed by extravasation of immunoglobulin G to the ischemic brain, was significantly reduced by MRE-269, which was associated with a reduction in matrix metalloproteinase-9 (MMP-9) activity in the brain of stroked aged rats given the IP agonist at 4.5h after ischemia onset. Our data suggest that targeting the IP receptor with MRE-269 is a novel strategy to reduce cerebral ischemia injury and promote long-term neurological recovery in ischemic stroke.
