Antinociceptive Effects of AS1892802, a Novel Rho Kinase Inhibitor, in Rat Models of Inflammatory and Noninflammatory Arthritis

Abstract

Rho kinase (ROCK) is involved in various physiological functions, including cell motility, vasoconstriction, and neurite extension. Although a functional role of ROCK in nociception in the central nervous tissue has been reported in neuropathy, the peripheral function of this protein in hyperalgesia is not known. In this study, antinociceptive effects of, a novel and highly selective ROCK inhibitor, were investigated in two rat models of arthritis. Orally administered AS1892802 exhibited potent antinociceptive effect in both an adjuvant-induced arthritis (AIA) model (inflammatory arthritis model) and a monoiodoacetate-induced arthritis (MIA) model (noninflammatory arthritis model), with an ED 50 of 0.15 mg/kg (MIA model). Fasudil, a ROCK inhibitor, and tramadol were also effective in both models; however, diclofenac was effective only in the AIA model. The onset of antinociceptive effect of AS1892802 was as fast as those of tramadol and diclofenac. AS1892802 did not induce gastric irritation or abnormal behavior. Because AS1892802 rarely penetrates the central nervous tissue and is also effective by intra-articular administration, it seemed to function peripherally. These results suggest that AS1892802 has an attractive analgesic profile for the treatment of severe osteoarthritis pain.

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

“…The plasma concentration of AS1892802 (1 mg/kg, orally administered) is enough to inhibit the ROCK activity (15). The Cmax of AS1892802 in the knee joint was estimated to be about half the plasma concentration and the rate of disappearance was slower from the knee joint than from plasma (our unpublished data).…”

“…In addition, expression of type II collagen mRNA continues to increase until the end of the 2-week period of treatment with AS1892802 in ATDC5 cells. In our previous studies, AS1892802 exhibited potent inhibitory activities for human ROCK I (IC 50 = 122 nM), human ROCK II (IC 50 = 52 nM), and rat ROCK II (IC 50 = 57 nM) (15), and 1 μM of AS1892802 (effective concentration in the ATDC5 cell studies) was enough high to inhibit ROCK activities in the neurite outgrowth assay using SH-SY5Y human neuroblastoma cells (15). Therefore, the ROCK activity was considered to be inhibited at 1 μM AS1892802 in cells.…”

“…The effective dose for pain reduction was lower than that for cartilage damage reduction. We have recently reported that a single dose of AS1892802 reduces both inflammatory and non-inflammatory pain (15) in rat models. The analgesic efficacy depended on blood concentration of the compound and maximum efficacy was obtained at the dose of 1 mg/kg (orally) 1 h after administration, but the activity disappeared within 24 h. In addition, analgesic activity was maintained by the repeated administration of the compound (41).…”

“…Therefore, AS1892802 is assumed to exhibit inhibitory effects on PGE 2 production of rabbit HIG82 cells via ROCK inhibition. The compound does not bind to bradykinin B 2 receptor (15). It is also reported to be an inhibitor of Rho- supplemented with 10% fetal calf serum and then the medium was replaced with serum-free Ham's F-12 medium containing 0.1% bovine serum albumin and various concentrations of AS1892802 and maintained for 24 h. PGE2 levels were determined in the supernatants using a commercial enzyme-linked immunosorbant assay kit.…”

“…Accordingly, pain remedies that are highly effective and have fewer adverse drug reactions are needed. We have found a potent and selective ROCK inhibitor, AS1892802, that reduces both inflammatory and non-inflammatory pain in rat models (15). Furthermore, drugs that suppress destruction of cartilage or promote its regeneration and thereby slow disease progression is highly desirable.…”