title: A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4.
abstract: Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca(2+); Mg(2+)) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca(2+) chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca(2+) chelating activities might confer greater safety over conventional tetracyclines.
authors.affiliation: Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Bloco A4, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
authors.forename: Leandro F S
authors.initials: LF
authors.lastname: Bastos
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Godin
authors.forename: Yingning
authors.initials: Y
authors.lastname: Zhang
authors.forename: Suwatchai
authors.initials: S
authors.lastname: Jarussophon
authors.forename: Bruno C S
authors.initials: BC
authors.lastname: Ferreira
authors.forename: Renes R
authors.initials: RR
authors.lastname: Machado
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Konishi
authors.forename: Rossimiriam P
authors.initials: RP
authors.lastname: de Freitas
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Márcio M
authors.initials: MM
authors.lastname: Coelho
authors.forename: Márcio F D
authors.initials: MF
authors.lastname: Moraes
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000293:injuries* / Q000503:physiopathology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014110:Touch
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D008911:Minocycline; D015232:Dinoprostone