Modulation of polymorphonuclear leukocyte responsiveness by copper (II)2 (niflumate)4 |
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| Authors: | M. Roch-Arveiller L. Maman D. P. Huy J. Fontagne J. -P. Giroud J. R. J. Sorenson |
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| Affiliation: | (1) Department of Pharmacology-CNRS URA 595, Hôpital Cochin, F-75014 Paris, France;(2) School of Dentistry, F-92120 Montrouge, France;(3) Center for Research of the Claude Bernard Association, Hôpital Cochin, F-75014 Paris, France;(4) Department of Medicinal Chemistry, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 West Markham Street, 72205 Little Rock, AR, USA |
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| Abstract: | Antiinflammatory activities and modulations of PMNL responses produced by treatment with tetrakis- -2-[3-(trifluoromethyl)-phenyl] aminonicotinatodicopper (II) [Cu(II)2(niflumate)4] and niflumic acid were studied in isologous serum-induced rat pleurisy. Doses of 10 or 30 mg/kg (35 or 106 µmol/kg) of niflumic acid or Cu(II)2 (niflumate)4 (8 or 23 µmol/kg) caused significant (p < 0.01) reductions in pleural exudate and number of polymorphonuclear leukocytes (PMNLs) in the exudate. While both doses of Cu(II)2(niflumate)4 produced significant dose-related reductions in both parameters, only the higher dose of niflumic acid produced a significant dose-related reduction in both parameters. Boyden chamber measurements of N-formyl-methionyl-leucyl-phenylalanine (f-MLP) chemotaxis by PMNLs incubated with 10 or 30 µg/ml niflumic acid (35 or 106 nmol/ml) or Cu(II)2(niflumate)4 (8 or 23 nmol/ml) were significantly (p < 0.01 to p < 0.001) decreased in dose-related fashions. Chemotaxis of PMNLs from pleuritic rats treated orally with 10 or 30 mg/kg niflumic acid or Cu(II)2(niflumate)4 was significantly (p < 0.001) inhibited by the larger dose of niflumic acid and both doses of Cu(II)2(niflumate)4. Opsonized zymosan (OZ)-stimulated chemiluminescence (CL) of PMNLs from pleuritic rats treated orally with these same doses of niflumic acid or Cu(II)2(niflumate)4 was only significantly (p < 0.05 or p < 0.01 respectively) decreased by the larger doses. Superoxide (O2-) production by these cells was significantly decreased by the larger dose of niflumic acid (p < 0.05) while both doses of Cu(II)2(niflumate)4 produced significant (p < 0.05 to p < 0.01) decreases. Recovery of the decreased PMNL response in burned rats was also studied following treatment with these two compounds. Oral treatment of non-burned rats with 1 mg/kg niflumic acid (4 µmol/kg) or Cu(II)2(niflumate)4 (1 µmol/kg) did not affect OZ-stimulated O2- production while decreased O2- production in non-treated scald-burned rats was reversed by oral treatment with either niflumic acid or Cu(II)2(niflumate)4. It is concluded that Cu(II)2(niflumate)4 is a more effective antiinflammatory agent than niflumic acid and more effective modulation of PMNL responsiveness may explain its beneficial antipleuritic and burn-injury recovery effects. Formation of the copper complex of niflumic acidin vivo may also account for its beneficial antiinflammatory effects and recovery of depressed PMNL responsiveness in burned rats. |
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| Keywords: | Pleurisy Burn Polymorphonuclear Copper niflumate |
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