Inhibition of microglial inflammation by the MLK inhibitor CEP-1347

Søren Lund, Peter Porzgen, Anne Louise Mortensen, Henrik Hasseldam, Donna Bozyczko-Coyne, Siegfried Morath, Thomas Hartung, Marina Bianchi, Pietro Ghezzi, Malika Bsibsi, Sipke Dijkstra, Marcel Leist

Research output: Contribution to journalArticle

Abstract

CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of Parkinson's disease (PD). Microglial activation may involve kinase pathways controlled by MLKs and might contribute to the pathology of neurodegenerative diseases. Therefore, the possibility that CEP-1347 modulates the microglial inflammatory response [tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1)] was explored. Indeed, the MLK inhibitor CEP-1347 reduced cytokine production in primary cultures of human and murine microglia, and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque forming peptide Aβ1-40. Moreover, CEP-1347 inhibited brain TNF production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways. These data imply MLKs as important, yet unrecognized, modulators of microglial inflammation, and demonstrate a novel anti-inflammatory potential of CEP-1347.

Original languageEnglish (US)
Pages (from-to)1439-1451
Number of pages13
JournalJournal of Neurochemistry
Volume92
Issue number6
DOIs
StatePublished - Mar 2005
Externally publishedYes

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Keywords

  • Alzheimer's disease
  • Central nervous system
  • CEP-1347
  • Inflammation
  • Microglia
  • Mixed lineage kinase
  • TNF-α

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Lund, S., Porzgen, P., Mortensen, A. L., Hasseldam, H., Bozyczko-Coyne, D., Morath, S., Hartung, T., Bianchi, M., Ghezzi, P., Bsibsi, M., Dijkstra, S., & Leist, M. (2005). Inhibition of microglial inflammation by the MLK inhibitor CEP-1347. Journal of Neurochemistry, 92(6), 1439-1451. https://doi.org/10.1111/j.1471-4159.2005.03014.x