RT Journal Article
SR Electronic
T1 <em>S</em>-Adenosyl-<span class="sc">l</span>-homocysteine Hydrolase Inhibitor Mediates Immunosuppressive Effects in Vivo: Suppression of Delayed Type Hypersensitivity Ear Swelling and Peptidoglycan Polysaccharide-Induced Arthritis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 106
OP 112
VO 296
IS 1
A1 Saso, Yoshihisa
A1 Conner, Elaine M.
A1 Teegarden, Bradley R.
A1 Yuan, Chong-Sheng
YR 2001
UL http://jpet.aspetjournals.org/content/296/1/106.abstract
AB A specific and potent inhibitor ofS-adenosyl-l-homocysteine (AdoHcy) hydrolase, 9-[(1′R,2′S,3′R)-2′,3′-dihydroxycyclopentanyl]adenine (DHCaA), was evaluated for its immunosuppressive efficacy on murine T-cell proliferation in vitro and in several animal models, including delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis. The concanavalin A-induced [3H]thymidine incorporation into T cells was strongly inhibited by DHCaA with a 50% inhibition concentration (IC50) of 0.3 μM. In vivo, a dose-dependent reduction (39, 62, and 73%) of ear swelling was observed when 2,4-dinitrofluorobenzene-treated mice were orally administered with DHCaA at 1, 5, and 10 mg/kg, respectively. This inhibition in ear swelling dose dependently corresponded to the inhibition of AdoHcy hydrolase activity in the spleen. The more potent the AdoHcy hydrolase inhibitor, the stronger the immunosuppressive efficacy observed. In rat peptidoglycan polysaccharide-induced arthritis, orally dosed DHCaA significantly suppressed inflamed paw volumes with minimal effective dose of 0.1 mg/kg. At a dose of 1 mg/kg, DHCaA almost completely inhibited paw swelling. This inhibition of paw swelling was associated with an inhibition of interleukin-1β production in joint tissues. Histopathological evaluation of the joints in rats treated with 1 mg/kg showed a significant improvement in the reduction of the histopathological grading score from untreated scores of 10.44 to 4.78. Results from this study indicate that inhibitors of AdoHcy hydrolase could be effective anti-inflammatory agents. The American Society for Pharmacology and Experimental Therapeutics