Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease.
As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P < 0.005; 10 months: 53% vs. 80%) and significantly (P < 0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 +/- 3 vs. 127 +/- 42; 10 months, 53 +/-5 vs. 140 +/- 37 mg/dl). Appearance of anti-DNA antibodies was retarded and survival significantly (P < 0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7 - 12-fold in 8- 10-month-old mice vs. 2-month-old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies proteinuria and survival of lupus mice, in an additional group of animals (N = 16). Thus, at 14.5 months when all mice given bindarit alone died, 50% of mice on combined therapy were still alive (P < 0.023). Studies are needed to establish whether bindarit may function as a steroid sparing drug in human lupus.
Zoja
C
C
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Corna
D
D
Benedetti
G
G
Morigi
M
M
Donadelli
R
R
Guglielmotti
A
A
Pinza
M
M
Bertani
T
T
Remuzzi
G
G
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001806:Blood Urea Nitrogen; D018932:Chemokine CCL2 / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control*; D008775:Methylprednisolone / Q000008:administration & dosage; D051379:Mice; D008814:Mice, Inbred NZB; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats
D000974:Antibodies, Antinuclear; D018932:Chemokine CCL2; D007191:Indazoles; D018836:Inflammation Mediators; D011422:Propionates; C079489:bindarit; D008775:Methylprednisolone