Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of alpha4 integrin.
OBJECTIVE
To determine the efficacy of a small molecule inhibitor of alpha4 integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE).


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-alpha4 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-alpha4 integrin treatments.


CONCLUSIONS
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).
Piraino
P S
PS
Department of Physiology and Pharmacology, University of Western Ontario, London, Canada.
Yednock
T A
TA
Freedman
S B
SB
Messersmith
E K
EK
Pleiss
M A
MA
Karlik
S J
SJ
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology; D003287:Contrast Media; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D005260:Female; D019786:Gadolinium DTPA; D006168:Guinea Pigs; D039441:Integrin alpha4 / Q000276:immunology / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D012720:Severity of Illness Index
D000906:Antibodies; D003287:Contrast Media; D039441:Integrin alpha4; D019786:Gadolinium DTPA