Pravastatin acute neuroprotective effects depend on blood brain barrier integrity in experimental cerebral ischemia.
Statins have since long been reported to exert acute neuroprotection in experimental stroke models. However, crucial questions still need to be addressed as far as the timing of their cerebral effects after intravascular administration and the role played by the blood brain barrier (BBB) crossing properties. We tested the effects of an hydrophilic statin (pravastatin, 100 nM), which poorly crosses BBB under physiological conditions. Pravastatin was administered either 90 min before or immediately after transient middle cerebral artery occlusion in the in vitro isolated guinea pig brain preparation. A multi-modal outcome assessment was performed, through electrophysiological and cerebral vascular tone recordings, MAP-2 immunohistochemistry, BBB evaluation via ZO-1/FITC-albumin analysis, AKT and ERK activation and whole-cell antioxidant capacity. Pravastatin pre-ischemic administration did not produce any significant effect. Pravastatin post-ischemic administration significantly prevented MAP-2 immunoreactivity loss in ischemic areas, increased ERK phosphorylation in the ischemic hemisphere and enhanced whole-cell antioxidant capacity. Electrophysiological parameters, vascular tone and AKT signaling were unchanged. In all tested ischemic brains, ZO-1 fragmentation and FITC albumin extravasation was observed, starting 30 min from ischemia onset, indicating loss of BBB integrity. Our findings indicate that the rapid anti-ischemic effects of intravascular pravastatin are highly dependent on BBB increased permeability after stroke.
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy. Electronic address: d.carone@campus.unimib.it.
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Carone
Unit of Experimental Epileptology and Neurophysiology, Fondazione Istituto Neurologico "C. Besta", Milan, Italy.
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Librizzi
Unit of Experimental Epileptology and Neurophysiology, Fondazione Istituto Neurologico "C. Besta", Milan, Italy.
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Cattalini
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Sala
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Conti
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy; PhD Program in Neuroscience, University of Milano Bicocca, Milan, Italy.
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Cuccione
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Versace
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Cai
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Monza
Unit of Experimental Epileptology and Neurophysiology, Fondazione Istituto Neurologico "C. Besta", Milan, Italy.
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de Curtis
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Ferrarese
Laboratory of Experimental Stroke Research, Milan Center for Neuroscience, Department of Surgery and Interdisciplinary Medicine, University of Milano Bicocca, Via Cadore 48, 20900 Monza, Milan, Italy.
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Beretta
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology* / Q000517:prevention & control; D002199:Capillary Permeability / Q000187:drug effects; D006168:Guinea Pigs; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D017035:Pravastatin / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D062826:Zonula Occludens-1 Protein; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D017035:Pravastatin
Acute stroke; Blood brain barrier; Intravascular administration; Neuroprotection; Statin