S-Adenosyl-L-homocysteine hydrolase inhibitor mediates immunosuppressive effects in vivo: suppression of delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis.
A specific and potent inhibitor of S-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 [(3)H]thymidine incorporation into T cells was strongly inhibited by DHCaA with a 50% inhibition concentration (IC(50)) of 0.3 microM. 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-1beta 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.
Saso
Y
Y
Tanabe Research Laboratories, USA, Inc., San Diego, California, USA. y-saso@tanabe.co.jp
Conner
E M
EM
Teegarden
B R
BR
Yuan
C S
CS
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000473:pathology / Q000517:prevention & control*; D004139:Dinitrofluorobenzene / Q000494:pharmacology; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D007596:Joints / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010457:Peptidoglycan; D011134:Polysaccharides; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000201:enzymology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D010457:Peptidoglycan; D011134:Polysaccharides; C054757:9-(2',3'-dihydroxycyclopent-4'-enyl)adenine; C065189:4',5'-didehydro-5'-deoxy-5'-fluoroadenosine; C081802:9-(2',3'-dihydroxycyclopentan-1'-yl)adenine; D004139:Dinitrofluorobenzene; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D013936:Thymidine