Tyrphostin AG490, a tyrosine kinase inhibitor, blocks actively induced experimental autoimmune encephalomyelitis.
Migration of lymphocytes from blood into the brain is a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous observations made in our laboratory showed that protein tyrosine kinase inhibitors were able to block lymphocyte adhesion to brain endothelium and prevent the entry of encephalitogenic T cell lines into the brain of SJL/J mice. Here we show that systemic administration of the protein tyrosine kinase inhibitor, tyrphostin AG490, blocks the development of actively induced EAE in a dose-dependent manner. Administration of 1 mg of drug daily significantly decreased the severity of the disease, while 3 mg of AG490 daily totally blocked the disease in 62% of treated animals, and in those that developed the disease, paralysis was delayed and clinical score was significantly reduced. Blood leukocytes isolated from mice treated with tyrphostin AG490 were less adhesive on VCAM-1 and fibronectin, when compared with control animals. AG490 treatment had no effect on the proliferation by antigen-stimulated peripheral lymph nodes cells. Interestingly, cells obtained from draining lymph nodes in AG490-treated animals and stimulated with antigen secreted two times more IFN-gamma and four times more IL-10, when compared with control animals, whereas no difference was observed in TNF-alpha production. Our results suggest that tyrphostin AG490 may have therapeutic potential by blocking tyrosine kinase activities involved in key mechanisms leading to demyelinating diseases of the central nervous system.
Constantin
G
G
Department of Pathology, Stanford University School of Medicine, Veterans Administration Medical Center, Palo Alto, USA. constant@borgoroma.univr.it
Brocke
S
S
Izikson
A
A
Laudanna
C
C
Butcher
E C
EC
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020032:Tyrphostins / Q000494:pharmacology* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016753:Interleukin-10; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases