Protective and anti-arthritic effects of deer antler aqua-acupuncture (DAA), inhibiting dihydroorotate dehydrogenase, on phosphate ions-mediated chondrocyte apoptosis and rat collagen-induced arthritis.
The effect of water extract of deer antler aqua-acupuncture (DAA; Cervi Pantotrichum Cornu) prepared from the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong in Korean), a traditional immunosuppressive and immunoactivating Korean herbal acupuncture [Int. Immunopharm. 3 7 (2003) 1001] on rat chondrocyte apoptosis was studied. Terminally differentiated hypertrophic chondrocytes were isolated from rat costochondrial cartilage and cell death was measured in the presence of 3-5 mM phosphate ions (Pi). The effect of 10 microg/ml DAA was compared to that of phosphonoformic acid (PFA), a competitive inhibitor of the Na-Pi co-transport on Pi-induced apoptosis in chondrocytes. A total of 1 mM PFA blocked anion-induced cell death and prevented an increase in the cell Pi content. In a parallel study, we determined that the DAA also protected chondrocytes from death. On the other hand, the effect of DAA was also evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase) and tested in the rat collagen-induced arthritis (CIA) model. Female 7-week-old Sprague-Dawley rats were used for the evaluation of DAA in the CIA model. Arthritis was evaluated by arthritis score, body weight loss, bone destruction score. DAA was administered by bilateral Shinsu (B23) acupuncture five times per week (10, 20, 30, and 100 microg/kg/day). DAA inhibited rat liver DHO-DHase in vitro with Ki = 843 +/- 43 microg/ml. The anti-proliferative effect of DAA was caused by cell cycle arrest at the S-phase. Treatment with 300 mg/kg/day of DAA completely prevented the development of CIA based on the reduction of the arthritis score. The 50% effective dose (ED50) of DAA on arthritis score was 64 mg/kg. DAA ameliorated body weight loss associated with disease onset. DAA suppressed the development of arthritis, even when it was administered after a booster immunization of collagen. DAA is a novel immunosuppressant which inhibits DHO-DHase and its effects in CIA suggest that it could be useful in the treatment of rheumatoid arthritis.
Kim
Kanp-Sung
KS
Department of Acupuncture-Moxibustion, Biochemistry and Molecular Biology, College of Oriental Medicine, Dongguk University and National Research Laboratory for Glycobiology, Sukjang-Dong 707, Kyungju City, Kyungbuk 780-714 South Korea.
Choi
Yoo-Haeng
YH
Kim
Kyung-Ho
KH
Lee
Young-Choon
YC
Kim
Cheorl-Ho
CH
Moon
Sang-Ho
SH
Kang
Seung-Goo
SG
Park
Young-Guk
YG
D026881:Acupuncture; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000999:Antlers / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000473:pathology; D003094:Collagen; D003670:Deer; D000090722:Dihydroorotate Dehydrogenase; D005260:Female; D017245:Foscarnet / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010710:Phosphates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters / Q000037:antagonists & inhibitors; D014020:Tissue Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D014867:Water
D000893:Anti-Inflammatory Agents; D000090722:Dihydroorotate Dehydrogenase; D007166:Immunosuppressive Agents; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; D014020:Tissue Extracts; D014867:Water; D017245:Foscarnet; D003094:Collagen; D044925:Oxidoreductases Acting on CH-CH Group Donors