Abstract
BackgroundAt low levels, carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties. However, the effect of CO-releasing molecule (CORM)-3, a water-soluble CORM, on ischemic stroke and its mechanism of action are still unclear.MethodsWe investigated the role of CORM-3 in the mouse model of transient middle cerebral artery occlusion (tMCAO). CORM-3 or saline was administered to mice by retro-orbital injection at the time of reperfusion after 1-h tMCAO or at 1 h after sham surgery. We assessed infarct volume and brain water content at 24 and 72 h after ischemia, blood-brain barrier permeability at 6 and 72 h after ischemia, and neurologic deficits on days 1, 3, 7, and 14.ResultsAmong mice that underwent tMCAO, those that received CORM-3 had significantly smaller infarct volume and greater expression of neuronal nuclear antigen (NeuN) and microtubule-associated protein 2 than did saline-treated mice. CORM-3-treated mice had significantly fewer activated microglia in the peri-infarction zone than did control mice and exhibited downregulated expression of ionized calcium-binding adapter molecule (Iba)-1, tumor necrosis factor-α, and interleukin 1β. CORM-3-treated mice had significantly lower brain water content and enhanced neurologic outcomes on days 3, 7, and 14 post-tMCAO. Lastly, CORM-3 treatment reduced Evans blue leakage; increased expression of platelet-derived growth factor receptor-β, tight junction protein ZO-1, and matrix protein laminin; and decreased protein level of matrix metalloproteinase-9.ConclusionCORM-3 treatment at the time of reperfusion reduces ischemia-reperfusion-induced brain injury by suppressing neuroinflammation and alleviating blood-brain barrier disruption. Our data suggest that CORM-3 may provide an effective therapy for ischemic stroke.
Highlights
At low levels, carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties
Carbon monoxide-releasing molecule-3 (CORM-3) treatment reduces cerebral infarct volume and increases protein levels of neuronal nuclear antigen (NeuN) and microtubule-associated protein 2 (MAP2) after transient middle cerebral artery occlusion (tMCAO) triphenyltetrazolium chloride (TTC) staining showed that the infarct volume of the tMCAO + saline group was significantly larger than that of the tMCAO + CO-releasing molecule (CORM)-3 group on days 1 and 3 after surgery (Fig. 1a–d)
Western blot analysis revealed that the expression levels of NeuN and MAP2 were significantly lower in the tMCAO + saline group than in the Sham + saline group on day 3
Summary
Carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties. Carbon monoxide-releasing molecules (CORMs), a group of compounds capable of carrying and liberating controlled quantities of CO, have shown promise for delivering exogenous CO without altering COHb to toxic levels [11, 18,19,20]. The mechanisms by which CORM-derived CO might offer its beneficial effects have not yet been thoroughly investigated, many studies substantiate the protective role of CORM-derived CO against cellular and tissue damage in numerous models of injury, such as renal ischemia-reperfusion injury, hemorrhagic stroke, traumatic brain injury, transplantation, sepsis, hypertension, and cardiovascular disorders [21,22,23,24,25,26,27,28]
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