Effect of synthetic matrix metalloproteinase inhibitors on lipopolysaccharide-induced blood-brain barrier opening in rodents: Differences in response based on strains and solvents.
Matrix metalloproteinase inhibitors (MMPIs) reduce blood-brain barrier (BBB) disruption and prevent cell death. Animal models of multiple sclerosis, cerebral ischemia and hemorrhage, and bacterial meningitis respond to treatment with MMPIs. We have used the intracerebral injection of lipopolysaccharide (LPS) in rat, which induces MMP production and results in a delayed opening of the BBB, to screen MMPIs to identify therapeutic agents. We hypothesized that the mouse would respond similarly to LPS and that the mouse/LPS model of BBB damage would be more useful for screening of MMPIs. Therefore, we adapted the rat LPS model to the mouse and compared the response to LPS and treatment with MMPIs. Wistar-Kyoto rats (WKY) and three strains of mice had stereotactic injections of LPS into the caudate. (14)C-sucrose was used to measure permeability of the BBB 24 h after injection. Initially, we tested three broad-spectrum MMPIs in the rat, BB-1101, BB-94, and BB-2293, and a MMP-2 selective inhibitor, IW449; both BB-1101 and BB-94 significantly suppressed LPS-induced BBB damage (p<0.05). In the 3 mouse strains, C57/BL6, C57/BL10, and C57/BL10HIIIR2, LPS significantly opened the BBB in C57/BL6, and it was the only strain that showed a reduction in BBB permeability with BB-94. Treatment with methylprednisolone and several broad-spectrum MMPIs, including BB-1101, was ineffective in the C57/BL6. There was a significant reduction in BBB permeability seen with 10% dimethyl sulfoxide (DMSO) alone, which was used to dissolve the selective MMP-2 and-9 inhibitor, SB-3CT. The tetracycline derivative, minocycline, reduced the BBB injury in mouse by blocking the production of MMP-9. Our results show variability in rats and mice to LPS and MMPIs, which most likely is based on genetic make-up. Understanding these differences may provide important clues that could guide selection of MMPIs in treatment of neurological diseases.
Rosenberg
Gary A
GA
Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. grosenberg@salud.unm.edu
Estrada
Eduardo Y
EY
Mobashery
Shahriar
S
D000818:Animals; D001593:Benzyl Compounds; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D003907:Dexamethasone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D012997:Solvents / Q000494:pharmacology; D013045:Species Specificity; D013386:Succinates; D013450:Sulfones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D012997:Solvents; D013386:Succinates; D013450:Sulfones; D013876:Thiophenes; D010649:Phenylalanine; D003907:Dexamethasone; C080985:batimastat; D020782:Matrix Metalloproteinases; D010431:Pentoxifylline; D004121:Dimethyl Sulfoxide