Inhibition of MMP2/MMP9 after spinal cord trauma reduces apoptosis.
METHODS
Randomized controlled trial.


OBJECTIVE
To characterize the increase in gelatinase A (MMP2) activity after spinal cord injury (SCI) in the mouse model, and the effects of MMP2/MMP9 inhibition on apoptotic cells.


BACKGROUND
Clinical consequences of SCI are due to a series of secondary injury cascades. Matrix metalloproteinases are thought play a key role in this, leading to apoptotic cell death.


METHODS
SCI via a drop tower in mice was used. MMP2 beta-gal reporter mice were used to quantify the level of MMP2 after SCI. In a follow-up experiment, mice which underwent SCI were randomized to daily SQ injections of MMP2/MMP9 inhibitor versus placebo. MMP2 levels were quantified and histology was performed with TUNEL and Luxol fast blue staining.


RESULTS
MMP2 transcription was significantly upregulated after SCI, by the beta-gal assay. Inhibition of MMP2/MMP9 activity after SCI led to statistically significant decreases in apoptosis within the zone of injury. There was a trend towards preservation of myelin by preserved luxol fast blue staining.


CONCLUSIONS
After SCI, MMP2 is upregulated along with neuron and glial cells apoptosis. The level of apoptosis could be reduced with MMP2/MMP9 inhibition. This supports MMP2 as cause for apoptosis after SCI with the potential for therapeutic intervention as apoptosis can be reduced with MMP2 inhibition.
Dang
Alexis B C
AB
Division of Orthopaedic Surgery, Veterans Affairs Medical Center, San Francisco, CA, USA.
Tay
Bobby K-B
BK
Kim
Hubert T
HT
Nauth
Aaron
A
Alfonso-Jaume
Maria Alexandra
MA
Lovett
David H
DH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D011897:Random Allocation; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9