TIMP-3 and MMP-3 contribute to delayed inflammation and hippocampal neuronal death following global ischemia.
Hippocampal neuronal death following transient global ischemia in the mouse takes days to occur, providing a potential timeframe for therapeutic intervention. Since matrix metalloproteinase-3 (MMP-3) enhances inflammation and tissue inhibitor of metalloproteinases-3 (TIMP-3) promotes apoptosis in ischemia, we hypothesized that they are involved in neuronal death secondary to transient global ischemia. Timp-3 knockout (T3KO) and wild type (T3WT) mice underwent 30 min bilateral carotid artery occlusion (BCAO), which causes hippocampal neuronal death 7 days after reperfusion. Mice lacking the Timp-3 gene have significantly less astrocytosis, microglial reactivity, MMP-3 activity and neuronal cell death. In addition, T3KO mice had decreased tumor necrosis factor (TNF) receptor-1 (TNFR1) expression and increased TNF-alpha converting enzyme (TACE) activity. Mmp-3 KO mice with a similar BCAO showed significantly fewer microglial cells, reduced TNF-alpha expression, and less neuronal death than the Mmp-3 WT. To see if TIMP-3 and MMP-3 cell death pathways were independent, we blocked MMPs with the broad-spectrum MMP inhibitor, BB-94, on days 3 through 6 of reperfusion in T3WT and T3KO mice. BB-94 rescued hippocampal neurons at 7 days in both T3WT and T3KO mice, but significantly fewer neurons died in T3KO mice treated with BB-94. Our results indicate a novel additive role for TIMP-3 and MMP-3 in delayed neuronal death, and show that delayed treatment with MMP inhibitors can be used to reduce hippocampal death.
Walker
Espen J
EJ
Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Rosenberg
Gary A
GA
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005911:Gliosis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D013876:Thiophenes / Q000494:pharmacology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D013876:Thiophenes; D019717:Tissue Inhibitor of Metalloproteinase-3; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D010649:Phenylalanine; C080985:batimastat; D051722:ADAM Proteins; D019278:Matrix Metalloproteinase 3; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse