Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IκBα degradation in a stimulus-specific manner in microglia
Version of Record online: 8 DEC 2005
Journal of Neurochemistry
Volume 96, Issue 2, pages 314–323, January 2006
How to Cite
Nikodemova, M., Duncan, I. D. and Watters, J. J. (2006), Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IκBα degradation in a stimulus-specific manner in microglia. Journal of Neurochemistry, 96: 314–323. doi: 10.1111/j.1471-4159.2005.03520.x
- Issue online: 8 DEC 2005
- Version of Record online: 8 DEC 2005
- Received August 4, 2005; revised manuscript received August 30, 2005; accepted August 31, 2005.
- inhibitor α of NF-κB (IκBα);
- mitogen-activated protein kinases;
- protein kinase C (PKC)
CNS inflammation mediated by microglial activation can result in neuronal and glial cell death in a variety of neurodegenerative and demyelinating diseases. Minocycline, a second-generation tetracycline, has profound anti-inflammatory properties in the CNS mediated, in part, by inhibition of microglia. MAPK and nuclear factor-κB (NF-κB) activation are hallmarks of activated microglia and they are critical for the expression of many inflammatory mediators. In the present study, we investigated minocycline effects on activation of p38, c-Jun-N-terminal activated protein kinase (JNK) 1/2 and extracellular signal regulated kinase (ERK) 1/2 MAPKs and inhibitor α of NF-κB (IκBα) degradation in BV-2 and primary microglial cells. Our results demonstrate that minocycline has the ability to inhibit all MAPKs but these effects strongly depend on the stimulus used for MAPK activation. Minocycline significantly decreased activation of all lipopolysaccharide-stimulated MAPKs but it was without effect on MAPKs activated by H2O2. Minocycline inhibited JNK1/2 and ERK1/2 but not p38 when stimulated by 2′,3′-O-(4-benzoylbenzoyl)-adenosine 5′-triphosphate, indicating that minocycline affects only certain upstream signaling target(s) that are stimulus-specific. Our data also suggest that protein kinase C (PKC) inhibition may be partially involved in the minocycline mechanism of MAPK inhibition. In addition, minocycline attenuated lipopolysaccharide-stimulated degradation of IκBα implying a possible inhibitory role on NF-κB transcriptional activity.