The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.
In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the MMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MMP inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease.
Lorenzl
Stefan
S
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.
Narr
Sabine
S
Angele
Barabara
B
Krell
Hans Willi
HW
Gregorio
Jason
J
Kiaei
Mahmoud
M
Pfister
Hans-Walter
HW
Beal
M Flint
MF
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D000818:Animals; D005260:Female; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010879:Piperazines / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D015996:Survival Rate; D013997:Time Factors
D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; C453902:Ro 28-2653; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9