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Published on: July 25, 2022
Inhibition of microglial inflammation by the MLK inhibitor CEP-1347
Søren Lund1, Peter Porzgen, Anne Louise Mortensen
1Disease Biology, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. sorl@lundbeck.com
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-alpha (TNF-alpha), 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 Abeta1-40. 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.
Insights
CEP-1347, a mixed lineage kinase inhibitor, reduces neuroinflammation by dampening microglial activation and pro-inflammatory cytokine production. This compound shows potential for treating neurodegenerative diseases like Parkinson's disease.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Mixed lineage kinases (MLKs) are MAPKKKs involved in cellular stress responses.
- MLK pathways in microglia may contribute to neuroinflammation and neurodegenerative disease pathology.
- CEP-1347 is a known inhibitor of MLKs, blocking neuronal apoptosis pathways.
Purpose of the Study:
- To investigate the effect of CEP-1347 on microglial inflammatory responses.
- To determine if CEP-1347 modulates pro-inflammatory cytokine production in microglia.
- To explore the potential of CEP-1347 as an anti-inflammatory agent in neuroinflammation.
Main Methods:
- Primary cultures of human and murine microglia were treated with endotoxins or Abeta1-40 peptide.
- Monocyte/macrophage-derived cell lines were also utilized.
- CEP-1347's effect on cytokine production (TNF-alpha, IL-6, MCP-1) and kinase activation (p38, c-Jun) was assessed.
- In vivo studies involved lipopolysaccharide injection in mice to measure brain TNF production.
Main Results:
- CEP-1347 significantly reduced pro-inflammatory cytokine production in activated microglia and macrophages.
- The compound inhibited TNF production in the mouse brain following lipopolysaccharide administration.
- CEP-1347 acted upstream of p38 and c-Jun activation, confirming its role as an MLK inhibitor in microglia.
Conclusions:
- Mixed lineage kinases are significant, previously unrecognized modulators of microglial inflammation.
- CEP-1347 exhibits novel anti-inflammatory properties by inhibiting microglial activation.
- These findings suggest CEP-1347 as a potential therapeutic candidate for neuroinflammatory conditions.
