title: Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies.
abstract: Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm3absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.|2 Milan Center for Neuroscience (NeuroMi), Milano, Italy.|3 Department of Neuroscience, San Gerardo Hospital, ASST Monza, Monza, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Beretta
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Versace
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.|2 Milan Center for Neuroscience (NeuroMi), Milano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Carone
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Riva
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Dell'Era
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cuccione
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Ruiyao
authors.initials: R
authors.lastname: Cai
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Monza
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pirovano
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Padovano
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stiro
authors.affiliation: 4 In vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS, San Raffaele Scientific Institute, Milano, Italy.|5 Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Presotto
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Paternò
authors.affiliation: 6 Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rossi
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.|2 Milan Center for Neuroscience (NeuroMi), Milano, Italy.|3 Department of Neuroscience, San Gerardo Hospital, ASST Monza, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Giussani
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.|2 Milan Center for Neuroscience (NeuroMi), Milano, Italy.|3 Department of Neuroscience, San Gerardo Hospital, ASST Monza, Monza, Italy.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sganzerla
authors.affiliation: 1 Laboratory of Experimental Stroke Research, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.|2 Milan Center for Neuroscience (NeuroMi), Milano, Italy.|3 Department of Neuroscience, San Gerardo Hospital, ASST Monza, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000628:therapy*; D002560:Cerebrovascular Circulation; D003097:Collateral Circulation / Q000187:drug effects*; D018475:Head-Down Tilt / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery; D010477:Perfusion; D051381:Rats; D020521:Stroke / Q000628:therapy*
keywords: Acute ischemic stroke; cerebral collaterals; collateral therapeutics; experimental stroke; ischemic penumbra