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.

Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling

“…TLR subfamily 4 (TLR4) is activated by pathogenic molecules such as LPS. Several studies have reported that drugs that reduce proinflammatory cytokine levels in vitro and in vivo via TLR4-dependent signaling pathways hold potential for treating neuroinflammation-linked neurodegenerative diseases [ 20 , 21 , 36 , 37 ]. For instance, MAO inhibitor treatment significantly reduces the LPS-induced increase in IL-1β and IL-6 mRNA levels, and IL-6 but not IL-1β levels are partially dependent on TLR4 signaling in BV2 microglial cells [ 37 ].…”

“…For instance, MAO inhibitor treatment significantly reduces the LPS-induced increase in IL-1β and IL-6 mRNA levels, and IL-6 but not IL-1β levels are partially dependent on TLR4 signaling in BV2 microglial cells [ 37 ]. In addition, the VEGFR antagonist sorafenib and ATP-sensitive potassium channel blocker gliquidone reduce proinflammatory cytokine levels in BV2 microglia cells via TLR4-linked signaling pathways [ 21 , 36 ]. In this study, treatment of BV2 microglial cells with LPS, TLR4 inhibitor, and nilotinib significantly downregulated LPS-evoked IL-1β levels compared with treatment with LPS and TLR4 inhibitor but not treatment with LPS and nilotinib, indicating that the effects of nilotinib on IL-1β levels are independent of TLR4 (Fig.…”

“…The mRNA levels of proinflammatory cytokines, Sod1, Sod2, Nlrp3, Nrf2, and Sirt3 in BV2 microglial cells and/or primary microglia/astrocytes were evaluated by real-time PCR as previously described [ 20 , 21 ]. In brief, cDNA synthesized with Superscript cDNA Premix Kit II (GeNetBio) was analyzed by 40-cycle real-time PCR using Fast SYBR Green Master Mix (Thermo Fisher Scientific, CA, USA) and a QuantStudio™ 5 system (Thermo Fisher Scientific).…”

“…For immunocytochemistry, cells fixed for 10 min in 4% paraformaldehyde were washed three times with PBS before incubation overnight with the appropriate primary antibody in GDB buffer as described previously [ 20 , 21 ]. The cells were subsequently washed with PBS and incubated at room temperature with the appropriate Alexa Fluor 488- or 555-conjugated secondary antibody for 2 h. Details of the antibodies are provided in Table 3 .…”

Computational Analysis of Pathogenetic Pathways in Alzheimer’s Disease and Prediction of Potential Therapeutic Drugs

“…Unexpectedly however, some of the drugs predicted to have a concordant signature with AD have previously been shown to be able to ameliorate the AD condition, as is the case for sorafenib [ 45 ] and montelukast [ 46 ]. Although this observation requires careful attention and validation in the in vivo setting, we may hypothesize that the pathways targeted by these drugs, rather than being pathological, may instead represent compensatory responses to the concomitant aberrant processes associated with the presence of fAD mutations.…”