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Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia

Baker, Andrew H., Sica, Vincenzo, Work, Lorraine M., Williams-Ignarro, Sharon, de Nigris, Filomena, Lerman, Lilach O., Casamassimi, Amelia, Lanza, Alessandro, Schiano, Concetta, Rienzo, Monica, Ignarro, Louis J., Napoli, Claudio
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.9 pp. 3597-3602
animal disease models, bioavailability, bone marrow, bone marrow cells, brain, brain damage, drugs, free radicals, gene transfer, genes, image analysis, infarction, interstitial collagenase, ischemia, nitric oxide, oxidants, patients, rats, stem cells, stroke, therapeutics
Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.