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.
Highlights
Neuroinflammation protects nervous tissue in the central nervous system (CNS) in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity [1]
Sorafenib pretreatment prevented the increase in COX-2 and IL-1b mRNA levels evoked by LPS but did not alter IL-6 and iNOS mRNA levels (Figures 1E, F and Supplementary Figure 1A)
We demonstrated that sorafenib, a multikinase inhibitor and anti-cancer drug, decreases the levels of proinflammatory cytokines as well as microglial and astrocyte activation induced by LPS
Summary
Neuroinflammation protects nervous tissue in the central nervous system (CNS) in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity [1]. In this process, microglia and astrocytes act as first responders [2]. Microglia actively survey various cues of the environment and significantly change their morphology in response to neural injury [3]. Activated microglia communicate with neighboring neurons and/or other glial cells, leading to the activation of and morphological changes in astrocytes, the most abundant cell type in the brain and supporters of neurons [4]. The identification of therapeutic molecular targets in the neuroinflammatory response would facilitate the development of drugs to prevent/ treat neuroinflammation-associated diseases
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