Chronic inflammatory response in the rat can be blocked by bindarit.
In the rat, injection of Freund's complete adjuvant was accompanied by a significant increase in concanavalin A (Con A)-reactivity of selected plasma proteins along with an increase in concentrations of selected proteins known as acute phase proteins. We have evaluated the effect of bindarit, (2-[(1-benzyl-indazol-3-yl)methoxy]-2-methyl propionic acid), on the expression of alpha 2-macroglobulin, a known acute-phase protein in the rat. This compound has previously been shown to inhibit heat-induced denaturation of rat serum albumin and to strongly reduce the secondary phase response of adjuvant induced arthritis. Adult rats were induced with chronic inflammation by injection with Freund's complete adjuvant. Bindarit was administered to the chronic inflamed rats as a 0.5% medicated diet. Indomethacin, given by gavage daily at a dose of 1 mg/kg body weight, was used as a reference drug. Qualitative and quantitative changes of Con A-reactive proteins and alpha 2-macroglobulin were examined by lectin- and immuno-blots, and by radioimmunoassay. It was noted that the concentration of alpha 2-macroglobulin increased in rats with adjuvant induced arthritis. The addition of bindarit and indomethacin were able to reduce the concentration of alpha 2-macroglobulin as well as the Con A-reactivity of various proteins to normal level 37 days following treatment. We have also examined the effects of chronic inflammation on the levels of rat clusterin, a testicular and serum glycoprotein related to programmed cell death, tissue regression, and complement cascade reaction; and testibumin, a testicular FSH and testosterone-responsive protein with unknown function. It was noted that chronic inflammation did not induce significant changes in both the clusterin and testibumin concentrations in these experimental groups. The involvement of protein glycosylation and denaturation in the production of new antigenic determinants, their role in the development of chronic inflammatory disease and the potential use of bindarit to investigate the relationship between abnormal glycosylation and autoimmune disease were discussed.
Guglielmotti
A
A
Population Council, New York, New York 10021.
Silvestrini
B
B
Saso
L
L
Zwain
I
I
Cheng
C Y
CY
D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy; D051152:Clusterin; D003208:Concanavalin A / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006023:Glycoproteins / Q000097:blood*; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D018832:Molecular Chaperones; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D049231:Saposins; D012709:Serum Albumin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism*
D000209:Acute-Phase Proteins; D051152:Clusterin; D006023:Glycoproteins; D007191:Indazoles; D018832:Molecular Chaperones; D011422:Propionates; D011506:Proteins; C483347:Psap protein, rat; D049231:Saposins; D012709:Serum Albumin; D000511:alpha-Macroglobulins; D003208:Concanavalin A; C079489:bindarit; D007213:Indomethacin