Effects of leflunomide on glomerulonephritis induced by antibasement membrane antibody in rats

Abstract

Leflunomide (HWA 486, a novel isoxazol derivative), shown to have potent immunosuppressant and antiinflammatory effects, was evaluated for its inhibitory and therapeutic effects on the glomerulonephritis induced in rats by rabbit antiserum against rat glomerular basement membrane. Leflunomide was administered orally to rats at 0.5 and 2 mg/kg/day for 20 days from 2 days before injection of the rabbit antiserum and at 2 mg/kg/day for 14 days from 5 days after the antibody injection. The present study consisting of 2 experiments for inhibitory (I) and therapeutic (II) effects of leflunomide revealed the following effects at 2 mg/kg: in experiment I, significant decreases in (a) urinary total protein, (b) plasma total cholesterol and fibrinogen and (c) thymus weight, and decreased incidences of fibrin deposits in Bowman's space, adhesion of the glomerulus to Bowman's capsule and deposition of rat IgG and C3; and in experiment II, decreases in (a), (b) and (c), though smaller than in experiment I, and decreases deposition of rat C3. Thus, leflunomide had potent inhibitory and limited therapeutic effects on glomerulonephritis, suggesting that the compound is effective in inhibiting the onset and development of glomerulonephritis.

Effects of leflunomide on immune responses and models of inflammation

“…Using an antibasement membrane antibody to induce glomerulonephritis in rats, Ogawa et al [22] showed that both preventive and curative therapy with leflunomide resulted in significant decreases in total urinary protein, plasma cholesterol and fibrogen, as well as decreased incidences of fibrin, IgG and C 3 deposits.…”

The Kynurenine Pathway

“…In 1998, leflunomide was approved by the FDA (USA) for the treatment of rheumatoid arthritis. Leflunomide has also been successful in inhibiting disease progression in animal models of autoimmune diseases, such as experimental autoimmune neuritis (Ogawa et al 1990), EAE (Bartlett et al 1993 and experimental myasthenia gravis (Vidic-Dankovic et al 1995). In a phase II trial recently, teriflunomide proved to be well tolerated and effective in reducing active lesions in patients with relapsing MS (O'Connor et al 2006).…”

Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes

“…In the search for new immunomodulatory drugs, recent preclinical and clinical trials revealed the potential of the isoxasol derivative leflunomide for the therapy of rheumatoid arthritis [1]. In addition, preclinical studies in animals have shown that leflunomide may favourably influence the course of several experimental autoimmune disorders such as tubulonephritis [2], glomerulonephritis [3], autoimmune uveitis [4], autoimmune encephalomyelitis [5], autoimmune manifestations in MRL/lpr mice [6] and autoimmune myocarditis [7]. Considering the effectiveness and good tolerability of the drug [1], these data predict a role for leflunomide in the treatment of autoimmune and other immunoinflammatory diseases.…”