Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia.
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.
Baker
Andrew H
AH
British Heart Foundation Glasgow Cardiovascular Research Centre, 126 University Place, Glasgow G12 8TA, United Kingdom.
Sica
Vincenzo
V
Work
Lorraine M
LM
Williams-Ignarro
Sharon
S
de Nigris
Filomena
F
Lerman
Lilach O
LO
Casamassimi
Amelia
A
Lanza
Alessandro
A
Schiano
Concetta
C
Rienzo
Monica
M
Ignarro
Louis J
LJ
Napoli
Claudio
C
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy*; D001973:Bromodeoxyuridine; D003131:Combined Modality Therapy / Q000379:methods*; D017931:DNA Primers; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020768:Middle Cerebral Artery / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology*
D017931:DNA Primers; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D009569:Nitric Oxide; D001973:Bromodeoxyuridine