Inhibition of microglial inflammation by the MLK inhibitor CEP‐1347

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-a (TNF-a), 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 Ab1-40. 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 antiinflammatory potential of CEP-1347.

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

“…Mitogen-activated protein kinases (MAPKs), the predominant signaling transduction pathway responsible for synthesis and production of proinflammatory factors in microglia, can be regulated by mitochondrial function (Akundi et al, 2005;Ciallella et al, 2005;Lund et al, 2005;Waetzig et al, 2005). In the present study, microglia were treated with rotenone (10 nM) for different intervals of time to determine the involvement of MAPK after rotenone stimulation.…”

“…However, the exact mechanism underlying the inhibition of microglial activation by opening mitoK ATP channels remains unknown. Mitochondrial membrane potential and the downstream MAPKs have been demonstrated to regulate microglial activation and the production of proinflammatory factors from microglia (Akundi et al, 2005;Ciallella et al, 2005;Lund et al, 2005;Waetzig et al, 2005). The inhibitory effects of IPT on rotenone-induced DC m loss and p38/JNK MAPK activation were abolished by addition of 5-HD, indicating IPT might regulate mitochondrial function and MAPKs pathways through opening mitoK ATP channels.…”

TLR2 Hypersensitivity of Astrocytes as Functional Consequence of Previous Inflammatory Episodes

“…IL-1 receptor antagonist (IL-1ra) and high-mobility group box 1 protein were purchased from R&D Systems (Wiesbaden, Germany); muramyl dipeptide and brefeldin A (BFA) were purchased from Sigma-Aldrich (Steinheim, Germany). The I-kB inhibitor Bay11-7082 (Merck, Darmstadt, Germany) and CEP1347 (Cephalon, West Chester, PA) (39,56,57) were added 30 min before the stimulus and remained present during the stimulation. Medium used in all experiments contained 2% FCS.…”

“…Subsequently, the stained Ags were imaged in the corresponding fields (channel 2). Based on these data sets, the nuclear translocation or intensities of NF-kB or phosphorylated c-Jun were quantified for each cell with the predefined algorithm "nuclear translocation," essentially as described earlier (4,39,57). NF-kB translocation.…”

Role of mitogen-activated protein kinase kinase kinases in signal integration

“…Small molecule inhibitors of MLKs have significant neuro-protective action in in vitro and animal models of neuronal apoptosis (Lund et al, 2005). CEP-1347, an indolocarbazole that is a derivative of the natural product K252a from the culture broth of the K252 strain of Nocardiopsis bacteria, inhibits MLKs and was well tolerated in human trials .…”