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Entrectinib attenuates LPS-induced neuroinflammation by inhibiting JNK, p38, and AKT pathways and ameliorates
Hanwoong Woo1, Sung Wook Kim2, Sohee Kim3
1Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, 24341, Republic of Korea.
Abstract:
Entrectinib, a Food and Drug Administration-approved medication for cancers such as non-small cell lung cancer, inhibits tropomyosin receptor kinases and penetrates the blood-brain barrier. Despite its approval, the effects of Entrectinib on neuroinflammatory responses and cognitive function within the central nervous system remain unclear. This study demonstrates that Entrectinib modulates lipopolysaccharide (LPS)-induced pro- and anti-inflammatory factors by suppressing JNK, p38, and AKT signaling, as well as NF-κB and STAT3 activity, in primary microglia. Entrectinib reduced CD16/32 levels, increased CD206 expression, enhanced phagocytic activity, and upregulated receptors and cytoskeletal genes in vitro. Additionally, Entrectinib decreased proinflammatory cytokines and inhibited JNK/p38/AKT and NF-κB/STAT3 signaling in the hippocampus of LPS-treated mice. Notably, Entrectinib ameliorated LPS-induced memory impairments in vivo. Collectively, these findings indicate that Entrectinib attenuates neuroinflammation and improves memory performance, supporting its potential therapeutic relevance for neuroinflammation-associated cognitive disorders.
Insights
Entrectinib, used for cancer, was found to reduce brain inflammation and improve memory in mice. This suggests potential benefits for cognitive disorders linked to neuroinflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Entrectinib is an FDA-approved cancer drug targeting tropomyosin receptor kinases.
- Its effects on central nervous system neuroinflammation and cognition are not well understood.
- Entrectinib crosses the blood-brain barrier, indicating potential neurological activity.
Purpose of the Study:
- To investigate Entrectinib's impact on neuroinflammatory responses.
- To assess Entrectinib's effects on cognitive function in the central nervous system.
- To elucidate the molecular mechanisms underlying Entrectinib's neuroprotective actions.
Main Methods:
- Primary microglia and hippocampus tissues from lipopolysaccharide (LPS)-treated mice were used.
- In vitro assays assessed inflammatory factor modulation, gene expression, and phagocytic activity.
- In vivo studies evaluated cognitive performance and molecular signaling pathways.
- Key signaling pathways studied included JNK, p38, AKT, NF-κB, and STAT3.
Main Results:
- Entrectinib modulated pro- and anti-inflammatory factors in microglia by suppressing JNK, p38, AKT, NF-κB, and STAT3 signaling.
- In vitro, Entrectinib reduced CD16/32, increased CD206, enhanced phagocytosis, and upregulated relevant genes.
- In vivo, Entrectinib decreased proinflammatory cytokines and inhibited the same signaling pathways in the hippocampus.
- Crucially, Entrectinib treatment ameliorated LPS-induced memory deficits in mice.
Conclusions:
- Entrectinib demonstrates significant neuroprotective properties by attenuating neuroinflammation.
- The drug enhances microglial function and modulates key inflammatory signaling pathways.
- Entrectinib improves memory performance, suggesting therapeutic potential for neuroinflammation-related cognitive impairments.
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