Dataset Information

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice.

ABSTRACT: Sorafenib is FDA-approved for the treatment of primary kidney or liver cancer, but its ability to inhibit many types of kinases suggests it may have potential for treating other diseases. Here, the effects of sorafenib on neuroinflammatory responses in vitro and in vivo and the underlying mechanisms were assessed. Sorafenib reduced the induction of mRNA levels of the proinflammatory cytokines COX-2 and IL-1β by LPS in BV2 microglial cells, but in primary astrocytes, only COX-2 mRNA levels were altered by sorafenib. Interestingly, sorafenib altered the LPS-mediated neuroinflammatory response in BV2 microglial cells by modulating AKT/P38-linked STAT3/NF-kB signaling pathways. In LPS-stimulated wild-type mice, sorafenib administration suppressed microglial/astroglial kinetics and morphological changes and COX-2 mRNA levels by decreasing AKT phosphorylation in the brain. In 5xFAD mice (an Alzheimer's disease model), sorafenib treatment daily for 3 days significantly reduced astrogliosis but not microgliosis. Thus, sorafenib may have therapeutic potential for suppressing neuroinflammatory responses in the brain.

SUBMITTER: Kim J

PROVIDER: S-EPMC8190398 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice.

Kim Jieun J Park Jin-Hee JH Park Seon Kyeong SK Hoe Hyang-Sook HS

Frontiers in immunology 20210527

Sorafenib is FDA-approved for the treatment of primary kidney or liver cancer, but its ability to inhibit many types of kinases suggests it may have potential for treating other diseases. Here, the effects of sorafenib on neuroinflammatory responses <i>in vitro</i> and <i>in vivo</i> and the underlying mechanisms were assessed. Sorafenib reduced the induction of mRNA levels of the proinflammatory cytokines COX-2 and IL-1β by LPS in BV2 microglial cells, but in primary astrocytes, only COX-2 mRNA ...[more]

PMID: 34122447

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Project description:BackgroundThe form(s) of amyloid-β peptide (Aβ) associated with the pathology characteristic of Alzheimer's disease (AD) remains unclear. In particular, the neurotoxicity of intraneuronal Aβ accumulation is an issue of considerable controversy; even the existence of Aβ deposits within neurons has recently been challenged by Winton and co-workers. These authors purport that it is actually intraneuronal APP that is being detected by antibodies thought to be specific for Aβ. To further address this issue, an anti-Aβ antibody was developed (MOAB-2) that specifically detects Aβ, but not APP. This antibody allows for the further evaluation of the early accumulation of intraneuronal Aβ in transgenic mice with increased levels of human Aβ in 5xFAD and 3xTg mice.ResultsMOAB-2 (mouse IgG2b) is a pan-specific, high-titer antibody to Aβ residues 1-4 as demonstrated by biochemical and immunohistochemical analyses (IHC), particularly compared to 6E10 (a commonly used commercial antibody to Aβ residues 3-8). MOAB-2 did not detect APP or APP-CTFs in cell culture media/lysates (HEK-APPSwe or HEK-APPSwe/BACE1) or in brain homogenates from transgenic mice expressing 5 familial AD (FAD) mutation (5xFAD mice). Using IHC on 5xFAD brain tissue, MOAB-2 immunoreactivity co-localized with C-terminal antibodies specific for Aβ40 and Aβ42. MOAB-2 did not co-localize with either N- or C-terminal antibodies to APP. In addition, no MOAB-2-immunoreactivity was observed in the brains of 5xFAD/BACE-/- mice, although significant amounts of APP were detected by N- and C-terminal antibodies to APP, as well as by 6E10. In both 5xFAD and 3xTg mouse brain tissue, MOAB-2 co-localized with cathepsin-D, a marker for acidic organelles, further evidence for intraneuronal Aβ, distinct from Aβ associated with the cell membrane. MOAB-2 demonstrated strong intraneuronal and extra-cellular immunoreactivity in 5xFAD and 3xTg mouse brain tissues.ConclusionsBoth intraneuronal Aβ accumulation and extracellular Aβ deposition was demonstrated in 5xFAD mice and 3xTg mice with MOAB-2, an antibody that will help differentiate intracellular Aβ from APP. However, further investigation is required to determine whether a molecular mechanism links the presence of intraneuronal Aβ with neurotoxicity. As well, understanding the relevance of these observations to human AD patients is critical.

Project description:Growing evidence indicates that disturbances in the inflammatory response system can have deleterious effects on neuronal function and mental health. While the correlation between elevated peripheral inflammatory markers and psychiatric disorders are well documented, the exact molecular and neuronal mechanism underlying the connection between activated inflammation and neuropsychiatric behaviour remain elusive. Microglia activation is the key interface between neuro-inflammation and manifestation of psychiatric symptoms. Microglia are immunocompetent cells in the central nervous system (CNS) which are primarily involved in the response to inflammatory stimulation and are widely used to study neuroinflammation and test anti-inflammatory chemicals. In the brain, activated microglia play very important roles during neuroinflammation and neurodegeneration. Both stress-related disorders such as Depression and PTSD, and medical conditions such as metabolic syndrome (Mets) and type 2 diabetes (TD2) are associated with increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) in circulation. This work was aimed at determining whether SFA interacts with LPS to activate microglia, thus up-regulating neuroinflammatory processes and, if so which pathways were involved in this process. Our results showed that low-dose LPS and palmitic acid (PA) robustly stimulated the expression of proinflammatory cytokines, and the combination of PA and LPS further upregulated proinflammatory cytokines through MAPK, NFκB and AP-1 signaling pathways in the HMC3-human microglial cell line. In addition, PA stimulated ceramide production via de novo synthesis and sphingomyelin hydrolysis, and the combination of LPS and PA further increased ceramide production. HMC3 co-cultured with macrophage and lymphocyte enhanced LPS and PA induced-inflammatory response more than that in HMC3 alone. These results indicate that LPS interacts with PA to activated microglia; induced neuroinflammatory responses, upregulate proinflammatory cytokine expression via MAPK, NFκB, and AP-1 signaling pathways, and induced sphingolipid metabolism in HMC3. These observations suggest that inhibiting microglia activation and reducing LPS and PA-induced inflammatory response may be useful in the treatment of neuronal inflammatory diseases.

Project description:BackgroundIn chronic myelogenous leukemia, reciprocal translocation between chromosome 9 and chromosome 22 generates a chimeric protein, Bcr-Abl, that leads to hyperactivity of tyrosine kinase-linked signaling transduction. The therapeutic agent nilotinib inhibits Bcr-Abl/DDR1 and can cross the blood-brain barrier, but its potential impact on neuroinflammatory responses and cognitive function has not been studied in detail.MethodsThe effects of nilotinib in vitro and in vivo were assessed by a combination of RT-PCR, real-time PCR, western blotting, ELISA, immunostaining, and/or subcellular fractionation. In the in vitro experiments, the effects of 200 ng/mL LPS or PBS on BV2 microglial cells, primary microglia or primary astrocytes pre- or post-treated with 5 µM nilotinib or vehicle were evaluated. The in vivo experiments involved wild-type mice administered a 7-day course of daily injections with 20 mg/kg nilotinib (i.p.) or vehicle before injection with 10 mg/kg LPS (i.p.) or PBS.ResultsIn BV2 microglial cells, pre- and post-treatment with nilotinib altered LPS-induced proinflammatory/anti-inflammatory cytokine mRNA levels by suppressing AKT/P38/SOD2 signaling. Nilotinib treatment also significantly downregulated LPS-stimulated proinflammatory cytokine levels in primary microglia and primary astrocytes by altering P38/STAT3 signaling. Experiments in wild-type mice showed that nilotinib administration affected LPS-mediated microglial/astroglial activation in a brain region-specific manner in vivo. In addition, nilotinib significantly reduced proinflammatory cytokine IL-1β, IL-6 and COX-2 levels and P38/STAT3 signaling in the brain in LPS-treated wild-type mice. Importantly, nilotinib treatment rescued LPS-mediated spatial working memory impairment and cortical dendritic spine number in wild-type mice.ConclusionsOur results indicate that nilotinib can modulate neuroinflammatory responses and cognitive function in LPS-stimulated wild-type mice.

Dataset Information

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice.

Publications

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice.

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