Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

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  • Takeshita Nobuaki
    Pharmacology Research Laboratories, Astellas Pharma, Inc., Japan
  • Yoshimi Eiji
    Pharmacology Research Laboratories, Astellas Pharma, Inc., Japan
  • Hatori Chie
    Pharmacology Research Laboratories, Astellas Pharma, Inc., Japan
  • Kumakura Fumiyo
    Pharmacology Research Laboratories, Astellas Pharma, Inc., Japan
  • Seki Nobuo
    Pharmacology Research Laboratories, Astellas Pharma, Inc., Japan
  • Shimizu Yasuaki
    Pharmacology Research Laboratories, Astellas Pharma, Inc., Japan

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Abstract

The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats. Our newly synthesized ROCK inhibitor, AS1892802, was injected into the ipsilateral knee or administered p.o. for 3 weeks. The compound dose-dependently and significantly inhibited of cartilage damage in the tibial plateau in a dose-dependent manner and decreased the weight distribution deficit associated with MIA injection. In addition, the compound also inhibited bradykinin induced pain responses in normal rats. In vitro, the compound could induce chondrocyte differentiation in a chondrogenic cell line and significantly inhibited IL-1β– or bradykinin-induced prostaglandin E2 production in a synovial cell line. AS1892802 prevents cartilage damage induced by MIA and has analgesic effects in rat pain models, suggesting that AS1892802 may be clinically useful for the treatment of OA.<BR>[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.10319FP]

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