Abstract WP297: Time-Dependent Effects of Drag-Reducing Polymers Administration on Permanent Middle Cerebral Artery Occlusion Injury in Rats

Abstract

Introduction: Current treatments for ischemic stroke are not focused directly on cerebral microcirculation. We previously showed that 2 μg/ml of drag-reducing polymers (DRPs) restore cerebral microcirculation and oxygenation in rats subjected to permanent middle cerebral artery occlusion (pMCAO). Here we evaluated the dependence of DRPs efficiency on stroke outcome from the time of application. Methods: DRPs (2 μg/ml) or saline was i.v. injected 0.5, 3, and 6 hrs after filament pMCAO in rats (n=10/group). In-vivo 2-photon laser scanning microscopy (2PLSM) was used to assess the acute effects of DRPs on cerebral microcirculation, hypoxia (NADH), and blood-brain barrier (BBB). Cerebral infarction, blood flow (CBF), and neurological outcomes were evaluated by magnetic resonance imaging (MRI) and behavioral testing, respectively, at 24 hours, 1 and 3 weeks after pMCAO. Differences between groups were determined using a two-way analysis of variance for multiple comparisons and posthoc testing with the statistical significance level set at p<0.05. Results: In vivo 2PLSM showed that pMCAO progressively decreased cerebral microcirculation leading to hypoxia and BBB disruption (p<0.05 from baseline). DRPs (0.5-6 hrs) increased near-wall blood flow velocity and flow rate in arterioles, leading to an increase in the number of erythrocytes entering capillaries, capillary perfusion and oxygenation while protecting BBB compared to saline (p<0.05). MRI demonstrated reduced infarct expansion (T2) and mitigated CBF disturbances (arterial spin labeling) in all DRPs-treated groups compared to saline (p<0.05). Neurobehavioral testing revealed more preserved neurological function in all DRPs groups than in the saline group (p<0.05). The obtained results showed that DRPs efficacy reduces with the time of application from 0.5 h to 6 hours after pMCAO but remains significant (p<0.05). Conclusions: DRPs (effectively restore cerebral microcirculation after pMCAO reducing tissue hypoxia and BBB damage, leading to reduced infarct size and improved neurological outcome in a time-dependent manner. DRPs can be used as a new effective adjunct therapy for ischemic stroke even without reperfusion and after delayed administration following the stroke onset.