Tissue inhibitor of metalloproteinase 1 inhibits excitotoxic cell death in neurons.
The upregulation of TIMP-1 following an excitotoxic injury has recently been hypothesized to be part of a general neuronal response that mediates long-lasting changes involved in tissue reorganization and possibly neuroprotection. In this study we have shown for the first time that within hours of applying TIMP-1 in recombinant form or by adenovirus-mediated gene transfer, neurons are highly protected against excitotoxic injury. Neither TIMP-3 nor a nonsecretable form of TIMP-1 protected neurons. TIMP-1 conferred highly significant protection to hippocampal cells exposed to a wide range of glutamic acid concentrations in both dissociated and organotypic hippocampal cultures. TIMP-1 did not prevent apoptotic cell death or death mediated by chemical ischemia. The observed neuroprotection may be explained by a decrease in calcium influx into neurons following stimulation with glutamate. These findings have a fundamental implication for our understanding of the physiological role of secreted TIMP-1 in the central nervous system.
Tan
Hiang Khoon
HK
University Research Centre for Neuroendocrinology and MRC Centre for Synaptic Plasticity, University of Bristol, Marlborough Street, Bristol BS2 8HW, UK.
Heywood
Darren
D
Ralph
G Scott
GS
Bienemann
Alison
A
Baker
Andrew H
AH
Uney
James B
JB
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000172:deficiency; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism; D009924:Organ Culture Techniques; D011190:Potassium Cyanide / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017470:Receptors, Glutamate; D011993:Recombinant Fusion Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D018698:Glutamic Acid; D020932:Nerve Growth Factor; D020782:Matrix Metalloproteinases; D011190:Potassium Cyanide; D002118:Calcium