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Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia
British Journal of Pharmacology
Journal Article Research Support, U.S. Gov't, P.H.S. --- Old month value: Jun
We tested the hypothesis that combined use of trophic factors and caspase inhibitors increases brain resistance to ischaemia in mice. Intracerebroventricular administration of bFGF (>10 ng) 30 min after MCA occlusion decreased infarct size and neurological deficit in a dose-dependent manner following 2 h ischemia and reperfusion (20 h). Combined administration of the subthreshold doses of bFGF (3 ng) and caspase inhibitors (z-VAD.FMK, 27 ng or z-DEVD.FMK, 80 mg) reduced infarct volume by 60%, and reduced neurological deficit. Treatment with a subthreshold dose of bFGF (3 ng) extended the therapeutic window for z-DEVD.FMK (480 ng) from 1 to 3 h after reperfusion. Caspase-3 activity in the ischaemic brain was increased 30 min and 2 h after reperfusion but, was significantly reduced in bFGF-treated animals by 29 and 16%, respectively. Caspase-3 activity was not reduced by a direct bFGF effect because addition of bFGF (10 nM - 2 microM) did not decrease recombinant caspase-3 activity, in vitro. Our data show that combining caspase inhibitors and bFGF lengthens the treatment window for the second treatment, plus lowers the dosage requirements for neuroprotection. These findings are important because low doses of caspase inhibitors or bFGF reduce the possibility of side effects plus extend the short treatment window for ischaemic stroke.
Amino Acid Chloromethyl Ketones/pharmacology/therapeutic use Animals Brain Ischemia/*drug therapy/enzymology/pathology Caspase 3 Caspases/*antagonists & inhibitors/metabolism Cysteine Proteinase Inhibitors/administration & dosage/*pharmacology/*therapeutic use Dose-Response Relationship, Drug Drug Synergism Drug Therapy, Combination Fibroblast Growth Factor 2/administration & dosage/*therapeutic use Male Mice Neuroprotective Agents/administration & dosage/pharmacology/*therapeutic use Oligopeptides/pharmacology/therapeutic use
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