Time-Dependent Efficiency of Drag-Reducing Polymers in Rat Model of Ischemic Stroke

Introduction:

Introduction: Current treatments for ischemic stroke are not focused on microvascular cerebral blood flow (mvCBF). We previously showed that drag-reducing polymers (DRP), injected just after permanent middle cerebral artery occlusion (pMCAO) in rats, effectively restored mvCBF and tissue oxygen supply via improving collateral microcirculation. Here, we evaluated the dependence of DRP efficiency on stroke outcome from the time of application after pMCAO.


Methods: DRP (2 μg/ml) or saline was injected intravenously 0.5, 3, or 6 hours after filament pMCAO in rats (n=10/group). In-vivo 2-photon laser scanning microscopy (2PLSM) was used to assess the acute effects of DRP 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: PMCAO progressively decreased cortical microcirculation, leading to tissue hypoxia and BBB disruption (p < 0.05 ). DRP (0.5-6 hours) increased near-wall blood flow velocity and flow rate in arterioles, leading to an increase in the number of erythrocytes entering capillaries, enhancing capillary perfusion and tissue 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 DRP groups compared to saline (p < 0.05) at 24 hours, 1, and 3 weeks after pMCAO. Neurological function was more preserved in all DRP groups than in the saline group (p < 0.05). In vivo 2PLSM, MRI, and neurobehavioral testing showed that DRP efficacy reduces with the time of application from 0.5 h to 6 hours after pMCAO but remains significant (p < 0.05).


Conclusions: DRP effectively restored cerebral microcirculation after pMCAO, reducing tissue hypoxia and BBB damage. This led to reduced infarct size and improved neurological outcomes in a time-dependent manner. DRP can be used as an adjunct therapy for ischemic stroke even without reperfusion and after delayed administration.