A novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice

• Published in: British journal of pharmacology Vol. 155; no. 5; pp. 714 - 721
• Main Authors: Bastos, L F S, Angusti, A, Vilaça, M C, Merlo, L A, Nascimento, E B, Rocha, L T S, Godin, A M, Solano, A G R, Jarussophon, S, Nunan, E A, Konishi, Y, Coelho, M M
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2008; Nature Publishing Group
• Subjects: 12S‐hydroxy‐1,12‐pyrazolinominocycline; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Calcium - metabolism; Cations, Divalent - metabolism; chelating activity; Chelating Agents - chemistry; Chelating Agents - pharmacology; chemically modified tetracyclines; cylinder‐plate assay; Edema - drug therapy; inflammation; Male; Medical sciences; Mice; Microbial Sensitivity Tests; minocycline; Minocycline - chemistry; Minocycline - pharmacology; Minocycline - therapeutic use; Molecular Structure; Motor Activity - drug effects; nociception; oedema; pain; Pain - drug therapy; Pain Measurement; Pharmacology. Drug treatments; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Research Papers; Rotarod Performance Test; Staphylococcus aureus; Staphylococcus aureus - drug effects; Nociception; oedema; chemically modified tetracyclines; Tetracycline derivatives; Rodentia; Inflammation; Tetracycline; cylinder-plate assay; Vertebrata; Antibiotic; Mammalia; Pain; Mouse; Animal; chelating activity; Minocycline; 12S-hydroxy-1,12-pyrazolinominocycline; Protein synthesis inhibitor; Antibacterial agent
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.303

Background and purpose:
Many in vitro and fewer in vivo studies have shown that tetracyclines present anti‐inflammatory activity. We investigated if a novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline, 12S‐hydroxy‐1,12‐pyrazolinominocycline (PMIN), also induced antinociceptive and anti‐inflammatory effects.
Experimental approach:
Antibacterial effects against a minocycline‐sensitive Staphylococcus aureus strain were evaluated by applying a cylinder‐plate agar diffusion technique. Antibacterial effects of diluted serum from mice pre‐treated with minocycline or PMIN were also evaluated. Ca2+ binding activity was assessed by spectrophotometry. Formalin‐induced nociceptive responses and carrageenan‐induced paw oedema were evaluated in mice. The rota‐rod apparatus was used to evaluate motor coordination.
Key results:
Minocycline, but not PMIN, inhibited bacterial growth. Serum from mice treated with minocycline, but not with PMIN, also induced such an effect. The UV absorption spectrum of solutions of minocycline, but not those of PMIN, was markedly changed in the presence of Ca2+. Minocycline or PMIN inhibited both phases of formalin‐induced nociception and carrageenan‐induced paw oedema. It is unlikely that antinociception resulted from lack of motor coordination, as tetracycline did not impair the performance of mice on the rotating rod.
Conclusions and implications:
These results indicate that inhibition of nociception and oedema by tetracyclines is neither necessarily linked to antibacterial nor to Ca2+chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the treatment of painful and inflammatory diseases, as its lack of antibacterial and Ca2+chelating activities might confer greater safety over conventional tetracyclines.
British Journal of Pharmacology (2008) 155, 714–721; doi:10.1038/bjp.2008.303; published online 28 July 2008