Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice
Jieun Kim1, Jin-Hee Park1, Seon Kyeong Park1
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea.
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.
Insights
Sorafenib, an FDA-approved cancer drug, shows potential in reducing neuroinflammation. It modulates key signaling pathways in microglial cells and suppresses inflammatory responses in mouse models, suggesting therapeutic applications beyond cancer treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Sorafenib is an FDA-approved kinase inhibitor for kidney and liver cancer.
- Its kinase inhibition profile suggests potential applications in other diseases, including those involving neuroinflammation.
Purpose of the Study:
- To investigate the effects of sorafenib on neuroinflammatory responses in vitro and in vivo.
- To elucidate the underlying molecular mechanisms of sorafenib's action on neuroinflammation.
Main Methods:
- Assessed sorafenib's impact on pro-inflammatory cytokine mRNA levels (COX-2, IL-1β) in LPS-stimulated BV2 microglial cells and primary astrocytes.
- Investigated modulation of AKT/P38-linked STAT3/NF-kB signaling pathways in BV2 cells.
- Administered sorafenib to LPS-stimulated wild-type mice and 5xFAD Alzheimer's disease model mice to evaluate in vivo effects on neuroinflammation.
Main Results:
- Sorafenib reduced COX-2 and IL-1β mRNA in microglial cells and COX-2 in astrocytes.
- Sorafenib modulated LPS-mediated neuroinflammation in microglial cells via AKT/P38-linked STAT3/NF-kB pathways.
- In vivo, sorafenib suppressed microglial/astroglial changes and COX-2 mRNA in wild-type mice by decreasing brain AKT phosphorylation.
- Sorafenib treatment reduced astrogliosis in 5xFAD mice but did not significantly affect microgliosis.
Conclusions:
- Sorafenib demonstrates neuroprotective and anti-neuroinflammatory effects.
- The drug modulates key signaling pathways involved in neuroinflammation.
- Sorafenib holds therapeutic potential for treating neuroinflammatory conditions, including Alzheimer's disease.
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