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Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of 4 integrin

Department of Physiology and Pharmacology, University of Western Ontario, Medical Sciences Building, Room 223, London, ON, Canada N6A 5C1

T A Yednock

Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, South San Francisco, CA, 94080, USA

S B Freedman

Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, South San Francisco, CA, 94080, USA

E K Messersmith

Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, South San Francisco, CA, 94080, USA

M A Pleiss

Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, South San Francisco, CA, 94080, USA

S J Karlik

Department of Physiology and Pharmacology, University of Western Ontario, Medical Sciences Building, Room 223, London, ON, Canada N6A 5C1, skarlik{at}uwo.ca

Purpose: To determine the efficacy of a small molecule inhibitor of ₄ integrin (CT301) at reversing the clinical, pathological and MR- detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE). Materials and methods: EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization. Animals received either saline (n=12), anti-₄ integrin antibody (AN100226m; n=12) or CT301 (n=12). T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for cerebral inflammation and gadolinium enhancement. T1-weighted images were further analyzed to quantify this enhancement as a measure of blood-brain barrier integrity. Dissected CNS was evaluated for inflammation and demyelination. Results: CT301 successfully reversed two clinical indicators of disease over the course of the treatment period. These animals showed decreased T2-weighted abnormalities, as well as a reduction in gadolinium leakage on T1-weighted images. Meningeal and perivascular inflammation was decreased by anti-₄ integrin treatments. Conclusion: CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in multiple sclerosis (MS).

Key Words: 4 integrin • experimental allergic encephalomyelitis • magnetic resonance imaging • multiple sclerosis • small molecule • therapeutic

Multiple Sclerosis, Vol. 11, No. 6, 683-690 (2005)
DOI: 10.1191/1352458505ms1223oa


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