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J Clin Invest. 1994 Dec; 94(6): 2177–2182.
PMCID: PMC330042

Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases.


Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inflammatory demyelination. A single dose of the inhibitor, given intraperitoneally, provided sufficient levels in the cerebrospinal fluid of animals with EAE to induce at least a partial inhibition of the gelatinase activity in the cerebrospinal fluid. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose-dependent way, respectively. Animals returned to the same clinical course as the nontreated group after cessation of treatment. Animals treated from the onset of clinical signs had normal permeability of the blood-brain barrier, compared with the enhanced permeability in nontreated animals. These results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease, since, the degree of demyelination and inflammation did not differ between the treatment groups.

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  • Steinman L, Miller A, Bernard CC, Oksenberg JR. The epigenetics of multiple sclerosis: clues to etiology and a rationale for immune therapy. Annu Rev Neurosci. 1994;17:247–265. [PubMed]
  • Banik NL. Pathogenesis of myelin breakdown in demyelinating diseases: role of proteolytic enzymes. Crit Rev Neurobiol. 1992;6(4):257–271. [PubMed]
  • Gijbels K, Masure S, Carton H, Opdenakker G. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J Neuroimmunol. 1992 Nov;41(1):29–34. [PubMed]
  • Gijbels K, Proost P, Masure S, Carton H, Billiau A, Opdenakker G. Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. J Neurosci Res. 1993 Nov 1;36(4):432–440. [PubMed]
  • Kleiner DE, Jr, Stetler-Stevenson WG. Structural biochemistry and activation of matrix metalloproteases. Curr Opin Cell Biol. 1993 Oct;5(5):891–897. [PubMed]
  • Mackay AR, Hartzler JL, Pelina MD, Thorgeirsson UP. Studies on the ability of 65-kDa and 92-kDa tumor cell gelatinases to degrade type IV collagen. J Biol Chem. 1990 Dec 15;265(35):21929–21934. [PubMed]
  • Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler-Stevenson WG. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res. 1992 Apr 3;576(2):203–207. [PubMed]
  • Schultz GS, Strelow S, Stern GA, Chegini N, Grant MB, Galardy RE, Grobelny D, Rowsey JJ, Stonecipher K, Parmley V, et al. Treatment of alkali-injured rabbit corneas with a synthetic inhibitor of matrix metalloproteinases. Invest Ophthalmol Vis Sci. 1992 Nov;33(12):3325–3331. [PubMed]
  • Grobelny D, Poncz L, Galardy RE. Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. Biochemistry. 1992 Aug 11;31(31):7152–7154. [PubMed]
  • Farrell CL, Stewart PA, Del Maestro RF. A new glioma model in rat: the C6 spheroid implantation technique permeability and vascular characterization. J Neurooncol. 1987;4(4):403–415. [PubMed]
  • Gijbels K, Van Damme J, Proost P, Put W, Carton H, Billiau A. Interleukin 6 production in the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol. 1990 Jan;20(1):233–235. [PubMed]
  • Rasminsky M. Pathophysiology of demyelination. Ann N Y Acad Sci. 1984;436:68–85. [PubMed]
  • McDonald WI, Miller DH, Barnes D. The pathological evolution of multiple sclerosis. Neuropathol Appl Neurobiol. 1992 Aug;18(4):319–334. [PubMed]
  • Youl BD, Turano G, Miller DH, Towell AD, MacManus DG, Moore SG, Jones SJ, Barrett G, Kendall BE, Moseley IF, et al. The pathophysiology of acute optic neuritis. An association of gadolinium leakage with clinical and electrophysiological deficits. Brain. 1991 Dec;114(Pt 6):2437–2450. [PubMed]
  • Waxman SG. Clinical course and electrophysiology of multiple sclerosis. Adv Neurol. 1988;47:157–184. [PubMed]
  • Sibley WA, Kiernat J, Laguna JF. The modification of experimental allergic encephalomyelitis with epsilon aminocaproic acid. Neurology. 1978 Sep;28(9 Pt 2):102–105. [PubMed]
  • Brosnan CF, Cammer W, Norton WT, Bloom BR. Proteinase inhibitors suppress the development of experimental allergic encephalomyelitis. Nature. 1980 May 22;285(5762):235–237. [PubMed]
  • Smith ME, Amaducci LA. Observations on the effects of protease inhibitors on the suppression of experimental allergic encephalomyelitis. Neurochem Res. 1982 May;7(5):541–554. [PubMed]
  • Inuzuka T, Sato S, Baba H, Miyatake T. Suppressive effect of camostat mesilate (FOY 305) on acute experimental allergic encephalomyelitis (EAE). Neurochem Res. 1988 Mar;13(3):225–228. [PubMed]
  • Murphy G, Atkinson S, Ward R, Gavrilovic J, Reynolds JJ. The role of plasminogen activators in the regulation of connective tissue metalloproteinases. Ann N Y Acad Sci. 1992 Dec 4;667:1–12. [PubMed]
  • Boehme DH, Umezawa H, Hashim G, Marks N. Treatment of experimental allergic encephalomyelitis with an inhibitor of cathepsin D (pepstatin). Neurochem Res. 1978 Apr;3(2):185–194. [PubMed]
  • Steinman L. The development of rational strategies for selective immunotherapy against autoimmune demyelinating disease. Adv Immunol. 1991;49:357–379. [PubMed]
  • Steinman L. Autoimmune disease. Sci Am. 1993 Sep;269(3):106–114. [PubMed]

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