semaxinib and Multiple-Sclerosis

What is the origin of the complex vascular changes that exist in the CNS lesions of Multiple Sclerosis (MS)? From the beginning of the study of the pathological changes in MS in the 19th century, lesions were seen to be associated with veins. On a microscopic level, there have been numerous pathological changes to these vessels including altered structure and permeability, fibrinolysis, iron-related alterations and collagen deposition. Vascular changes in inflammatory conditions outside the CNS are well documented and we hypothesize that angiogenesis (the generation of new blood vessels from existing) is an integral process of lesion development and spread in MS. We demonstrated similar vascular abnormalities in MS and in the animal model, EAE. We measured the increase in angiogenesis-related genes in EAE and review herein the effectiveness of chemical inhibitors of angiogenesis (SU5416, thalidomide and several derivatives). We postulate that interference with angiogenesis provides a suitable non-immunological target for investigation in MS.

Topics: Angiogenesis Inhibitors; Animals; Drug Delivery Systems; Encephalomyelitis, Autoimmune, Experimental; Humans; Indoles; Multiple Sclerosis; Pyrroles; Thalidomide

The known KDR inhibitor SU5416 and several analogues of the indolin-2-one family were surprisingly found to be highly efficacious in the EAE model, an established model for multiple sclerosis. The high in vivo effect could be correlated to in vitro inhibition of the pro-inflammatory cytokine IL-2. Activity following po administration was obtained with several analogues and via the use of prodrugs.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; In Vitro Techniques; Indoles; Interleukin-2; Leukocytes, Mononuclear; Mice; Multiple Sclerosis; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2