A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4

•12S-Hydroxy-1,12-pyrazolinominocycline (PMIN) is a non-antibacterial tetracycline.•PMIN or minocycline partially reverses nerve injury-induced allodynia in mice.•PMIN or minocycline reduces LPS-induced PGE2 production by rat microglial cells.•PMIN or minocycline inhibits signaling via human TLR2 an...

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Bibliographic Details
Published in:Neuroscience letters 2013-05, Vol.543, p.157-162
Main Authors: Bastos, Leandro F.S., Godin, Adriana M., Zhang, Yingning, Jarussophon, Suwatchai, Ferreira, Bruno C.S., Machado, Renes R., Maier, Steven F., Konishi, Yasuo, de Freitas, Rossimiriam P., Fiebich, Bernd L., Watkins, Linda R., Coelho, Márcio M., Moraes, Márcio F.D.
Format: Article
Language:English
Subjects:
12S-Hydroxy-1,12-pyrazolinominocycline
Animals
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Cells, Cultured
Chemically modified tetracycline
Dinoprostone - biosynthesis
Female
Humans
Hyperalgesia - drug therapy
Hyperalgesia - physiopathology
Lipopolysaccharides - pharmacology
Mice
Mice, Inbred C57BL
Microglia - drug effects
Microglia - metabolism
Minocycline - pharmacology
Minocycline - therapeutic use
Neuralgia - drug therapy
Neuralgia - physiopathology
Neuropathic pain
PGE2
Physical Stimulation
Rats
Rats, Wistar
Sciatic Nerve - injuries
Sciatic Nerve - physiopathology
Signal Transduction
TLR2
TLR4
Toll-Like Receptor 2 - metabolism
Toll-Like Receptor 4 - metabolism
Touch
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Summary:•12S-Hydroxy-1,12-pyrazolinominocycline (PMIN) is a non-antibacterial tetracycline.•PMIN or minocycline partially reverses nerve injury-induced allodynia in mice.•PMIN or minocycline reduces LPS-induced PGE2 production by rat microglial cells.•PMIN or minocycline inhibits signaling via human TLR2 and TLR4.•PMIN might be a safe novel anti-inflammatory pain suppressive drug. 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 (Ca2+; Mg2+) 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; 23.75mg/kg, 47.50mg/kg or 95.00mg/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 Ca2+ 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 Ca2+ chelating activities might confer greater safety over conventional tetracyclines.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2013.03.014