Characterisation of matrix metalloproteinases and the effects of a broad-spectrum inhibitor (BB-1101) in peripheral nerve regeneration.
The effect of treatment with a broad-spectrum inhibitor (BB1101) of the matrix metalloproteinases (MMPs) on nerve regeneration and functional recovery after nerve crush was examined. Drug treatment had no effect on latency but from 63 days the compound muscle action potential was significantly increased and was no different to that in the sham-operated controls at 72 days. Levels of MMP mRNA expression, and the localisation and activity of MMP proteins, were examined in rats for a 2 month period following a nerve crush injury, and compared with sham-operated controls. The mRNA of all the MMPs studied was up-regulated by 5-10 days after nerve crush, and they remained up-regulated for 40-63 days, except for MMP-9 which was down-regulated by 10 days. MMP immunoreactivity was localised to Schwann cells, macrophages and endothelial cells, and with the exception of membrane type 1-MMP (MT1-MMP), it was more intense after nerve crush compared with sham-operated controls. Regenerating axons showed immunoreactivity for MMP-2 and MMP-3. In situ zymography confirmed that the activity of MMPs in the nerve was increased following crush but that the activity was greatly reduced in rats treated with BB-1101. Thus despite the inhibition of MMPs by BB-1101, the drug did not appear to essentially affect nerve degeneration or regeneration following nerve crush but that it could be beneficial in promoting the more effective reinnervation of muscles possibly by actions at the level of the muscles.
Demestre
M
M
Department of Clinical Neurosciences, Guy's, King's and St. Thomas' School of Medicine, Guy's Campus, London SE1 1UL, UK. m.demestre@qmul.ac.uk
Wells
G M
GM
Miller
K M
KM
Smith
K J
KJ
Hughes
R A C
RA
Gearing
A J
AJ
Gregson
N A
NA
D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000473:pathology; D001593:Benzyl Compounds; D003907:Dexamethasone / Q000494:pharmacology*; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009132:Muscles / Q000503:physiopathology; D009186:Myelin Sheath / Q000473:pathology; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000503:physiopathology; D009416:Nerve Regeneration / Q000187:drug effects*; D009431:Neural Conduction / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000503:physiopathology*; D013386:Succinates; D014018:Tissue Distribution
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D013386:Succinates; D003907:Dexamethasone; D010447:Peptide Hydrolases; D020782:Matrix Metalloproteinases; D010431:Pentoxifylline