title: The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenic ALS mice.
abstract: 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.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.forename: Sabine
authors.initials: S
authors.lastname: Narr
authors.forename: Barabara
authors.initials: B
authors.lastname: Angele
authors.forename: Hans Willi
authors.initials: HW
authors.lastname: Krell
authors.forename: Jason
authors.initials: J
authors.lastname: Gregorio
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: 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
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; C453902:Ro 28-2653; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9