Suppression of experimental autoimmune encephalomyelitis by tyrphostin AG-556

Tyrosine kinase blockers from the AG 126/AG-556 tyrphostin family are shown to inhibit the lipopolysaccharide (LPS)-induced production of tumor necros is factor alpha (TNF alpha), nitric oxide (NO), and prostaglandin E-2 (PGE( 2)) in primary rat astrocytes cultures. The tyrphostin AG-556 which was pre viously shown to be effective against sepsis in mice and dogs also show exc ellent efficacy in inhibiting experimental autoimmune encephalomyelitis (EA E) in mice. AG-556 does not block the activation of JNK/SAPK and of p38/HOG and therefore seems to act at a target down stream to these kinases which is activated in stress or at a target on an obligatory parallel pathway. Th ese findings together with previous results showing inhibition of sepsis in mice and dogs suggest that protein tyrosine kinase (PTK) blockers of the A G-556 family may be considered in the management of human autoimmune disord ers such as multiple sclerosis (MS). (C) 1998 Academic Press.