title: Cerebral collateral flow defines topography and evolution of molecular penumbra in experimental ischemic stroke.
abstract: 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 regard to penumbral tissue after transient middle cerebral artery (MCA) occlusion in rats. MCA was transiently occluded (90min) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in terms of perfusion deficit and biosignal fluctuation analyses using multi-site laser Doppler monitoring. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of Heat Shock Protein 70kDa (HSP70) immunohistochemistry. Functional deficit and infarct volume were assessed 24h after ischemia induction. The results show that functional performance of intracranial collaterals during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both the cortex and the striatum, as well as with infarct size and functional deficit. Intracranial collateral flow was 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.
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy; Milan Center for Neuroscience (NeuroMi), Milano, Italy. Electronic address: simone.beretta@unimib.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Beretta
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy; PhD Programme in Neuroscience, University of Milano Bicocca, Monza, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cuccione
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Versace
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Carone
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Riva
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Padovano
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Dell'Era
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Ruiyao
authors.initials: R
authors.lastname: Cai
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Monza
authors.affiliation: Department of Nuclear Medicine, San Raffaele Scientific Institute, Milan, Italy; Institute of Bioimaging and Molecular Physiology, National Research Council, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Presotto
authors.affiliation: Université de Lyon, CREATIS, CNRS UMR5220, Inserm U1044, INSA-Lyon, Université Lyon 1, France.
authors.forename: David
authors.initials: D
authors.lastname: Rousseau
authors.affiliation: Université de Lyon, CREATIS, CNRS UMR5220, Inserm U1044, INSA-Lyon, Université Lyon 1, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Chauveau
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Paternò
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Pappadà
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Giussani
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sganzerla
authors.affiliation: Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy; Milan Center for Neuroscience (NeuroMi), Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002339:Carotid Arteries / Q000503:physiopathology; D002340:Carotid Artery Diseases; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D017078:Laser-Doppler Flowmetry; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017208:Rats, Wistar; D012720:Severity of Illness Index; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*
chemical_list: D034961:Antigens, Nuclear; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; C546339:Rbfox3 protein, rat
keywords: Cerebral collaterals; Hemodynamic changes; Neuroprotection; Penumbra; Stroke