Introduction: Tissue plasminogen activator is used in only 5% of stroke patients because therapeutic window is short (∼3 hr) due to risk of hemorrhage. Rheological modulation of blood flow by nanomolar concentrations of drag-reducing polymers (DRP) improved hemodynamics and survival in animal models of the ischemic myocardium and limb. We previously showed that DRP applied early at 30 min after permanent middle cerebral artery occlusion (pMCAO) restored microvascular perfusion and improved neurologic outcome. We hypothesized that DRP applied after 3 hr delay would be effective in improving recovery.
Methods: DRP or saline (control) were i.v. injected 3 hours after pMCAO in rats. Evaluation of the acute DRP effects (5 hours after pMCAO) on microvascular perfusion, hypoxia (NADH) and blood brain barrier (BBB) was done by in-vivo 2-photon laser scanning microscopy (2PLSM) and followed by brain perfusion for Fluoro-Jade staining for neurodegeneration. Cerebral infarction and perfusion were evaluated by MRI at 24 hours, 1 and 3 weeks after pMCAO. Motor function was evaluated by Rotarod test at 1, 2 and 3 weeks after pMCAO.
Results: DRP compared to saline, applied after 3 hours following pMCAO, improved impaired microvascular circulation in the penumbra of the parietal cortex (Δ=33 %), reducing hypoxia (Δ=27 %) and BBB damage (Δ=42 %) thereby protecting neurons from neurodegeneration (Fluoro-Jade, Δ=36 %) (n=4, p<0.05). After prolonged recovery, DRP solution compared to saline reduced infarct expansion (Δ=23 %) and increased cerebral blood flow (Δ=31 %) in the penumbra at 24 hours, 1 and 3 weeks after pMCAO as measured by MRI (n=6, p<0.05). Rotarod tests showed that DRP treated rats performed better than saline treated (Δ=35 %) at 1, 2 and 3 weeks after the pMCAO (n=6, p<0.05).
Conclusions: Rheological enhancement of cerebral microcirculation by DRP improved neurologic outcome after permanent MCAO without reperfusion even with delayed application after stroke onset. Potential DRP mechanisms involve improved collateral flow and anti-inflammatory effects of the increased shear stress with enhanced microcirculatory flow. DRP may be an effective therapy for ischemic stroke even without reperfusion and after delayed administration following the stroke onset.