Intracranial collateral flow defines the boundaries of molecular penumbra in experimental ischemic stroke

Objective: Intracranial collaterals are dynamically recruited after arterial occlusion and are emerging as a strong determinant of tissue outcome in both human and experimental ischemic stroke. The relationship between collateral flow and ischemic penumbra remains largely unexplored in pre-clinical studies. The aim of the present study was to investigate the pattern of collateral flow with regards of penumbral tissue in rats after transient middle cerebral artery (MCA) occlusion. Materials and methods: MCA was transiently occluded (90 minutes) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in term of perfusion deficit and biosignal fluctuation analysis using multi-site laser Doppler monitoring in the borderzone territory between MCA and anterior cerebral artery and in the central MCA territory. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of HSP70 immunohistochemistry. Functional deficit was assessed using a 18-points sensory-motor score and infarct volume was calculated on consecutive sections stained with Cresyl violet, performed 24 hours after ischemia induction. Results: The degree of functional performance of intracranial collaterals in the territory of leptomeningeal branches during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both cortex and striatum, as well as with infarct size and functional deficit, and predicted of the amount of intact tissue after MCA occlusion followed by reperfusion. Conclusions: Intracranial collateral flow is associated with reduced areas of both molecular penumbra and ischemic core and increased areas of intact tissue in rats subjected to MCA occlusion followed by reperfusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy.