Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice

Echeverrı́a, Valentina; Burgess, Sarah; Gamble-George, Joyonna; Zeitlin, Ross; Lin, Xiaoyang; Cao, Chuanhai; Arendash, Gary W.

doi:10.1016/j.neuroscience.2009.05.019

Cited by 66 publications

(49 citation statements)

References 66 publications

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“…61 It is also reported that Sorafenib can protect against ischemia/reperfusion (IR) injury in rats with nonalcoholic steatohepatitis, 62 is able to reverse LPS-induced hypotension by targeting soluble epoxide hydrolase (sEH), an enzyme with pleiotropic effects on inflammation and vascular disease, 63 and is also able to restore working memory abilities in a mouse model for Alzheimer’s disease (AD) by inhibition of the pro-neuroinflammatory factor cRaf-1 and NF- κ B. 64 Thus Sorafenib exerts an anti-inflammatory activity in other in vivo experimental diseases models. Given the inflammatory response triggered by release of cytokines, chemokines and DAMPs from necroptotic dying cells, 42, 59 these reported anti-inflammatory effects of Sorafenib in vivo may be attributed to its potent necroptosis targeting effect we describe here.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

et al. 2017

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Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-κB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia–reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology.

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Section: Discussionmentioning

confidence: 99%

Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

et al. 2017

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“…These results and our in vitro data showing that vandetanib reduces endothelial cell Akt phosphorylation and nitrite production suggest that VEGFR2 inhibition reduces constitutive eNOS-mediated NO production. Other sources of NOx are less likely to contribute to this picture as VEGFR2 inhibition has been shown to decrease inducible NOS (36). Thus, our data are consistent with a mechanism of VEGFR2 inhibition disrupting the PI3K-Akt-HSP90 phosphorylation-dependent activation of eNOS, leading to chronically reduced NO levels and hypertension, particularly in light of other work in humans demonstrating no change in sympathetic nervous system, renin-angiotensin system, and endothelin 1 humoral activity (15).…”

Section: Discussionmentioning

confidence: 99%

Contrary Effects of the Receptor Tyrosine Kinase Inhibitor Vandetanib on Constitutive and Flow-Stimulated Nitric Oxide Elaboration in Humans

et al. 2011

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Vascular endothelial growth factor regulates neoplastic angiogenesis through production of endothelium-derived nitric oxide. We performed a prospective evaluation of vascular function during treatment with vandetanib, a vascular endothelial growth receptor 2 and 3 receptor tyrosine kinase inhibitor, to determine the effects of vascular endothelial growth receptor signal interruption on endothelial function in humans. Seventeen patients with stage IV breast cancer received dose escalated vandetanib in combination with low-dose oral chemotherapy. We measured blood pressure, systemic nitrate/nitrite levels, and brachial artery vascular function. In vitro analyses of cultured endothelial cells were performed to determine the effect of vandetanib on nitric oxide production, akt473 phosphorylation, and endothelial nitric oxide synthase protein content and membrane localization. Vandetanib treatment for 6 weeks significantly increased blood pressure, decreased resting brachial artery diameter, and decreased plasma systemic nitrate/nitrite levels compared to baseline. Flow-mediated vasodilation was preserved, and no change was noted in nitroglycerin-mediated vasodilation. In vitro, endothelial cell nitrite levels and akt473 phosphorylation were reduced, vascular endothelial growth receptor 2 levels did not change, but endothelial nitric oxide synthase membrane concentration doubled. Vandetanib reduces constitutive nitric oxide production and increases blood pressure, yet flow-stimulated nitric oxide bioavailability was preserved. Changes in vascular function with tyrosine kinase inhibition are complex and require further study in humans.

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“…Brain tissues from mice in protocol 1 were analyzed by Western blot as previously described (Echeverria et al, 2009). Brains were rapidly removed and tissues dissected and disrupted by sonication in RIPA buffer (Cell Signaling Technology, Danvers, MA) with a complete protease inhibitor cocktail (Roche Molecular Biochemicals).…”

Section: Methodsmentioning

confidence: 99%

Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice

Patel

Grizzell

Holmes

et al. 2014

Front. Aging Neurosci.

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Alzheimer's disease (AD) is associated with cognitive and non-cognitive symptoms for which there are currently no effective therapies. We have previously reported that cotinine, a natural product obtained from tobacco leaves, prevented memory loss and diminished amyloid-β (Aβ) plaque pathology in transgenic 6799 mice (Tg6799 mice) when treated prior to the development of the pathology. We have also shown that cotinine reduces depressive-like behavior in normal and chronically stressed C57BL/6 mice. Here, we extend our previous studies by investigating the effects of cotinine on the progression of AD-like pathology, depressive-like behavior, and the mechanisms underlying its beneficial effects in Tg6799 mice when left untreated until after a more advanced stage of the disease's development. The results show that vehicle-treated Tg6799 mice displayed an accentuated loss of working memory and an abundant Aβ plaque pathology that were accompanied by higher levels of depressive-like behavior as compared to control littermates. By contrast, prolonged daily cotinine treatment to Tg6799 mice, withheld until after a mid-level progression of AD-like pathology, reduced Aβ levels/plaques and depressive-like behavior. Moreover, this treatment paradigm dramatically improved working memory as compared to control littermates. The beneficial effects of cotinine were accompanied by an increase in the expression of the active form of protein kinase B and the postsynaptic density protein 95 in the hippocampi and frontal cortices of Tg6799 mice. This suggests that cotinine halts the progression of AD-like pathology while reducing depressive-like behavior by stimulating signaling pathways supporting synaptic plasticity in Tg6799 mice. The potential use of cotinine to treat cognitive and non-cognitive symptoms of AD is discussed.

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Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice

Cited by 66 publications

References 66 publications

Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

Contrary Effects of the Receptor Tyrosine Kinase Inhibitor Vandetanib on Constitutive and Flow-Stimulated Nitric Oxide Elaboration in Humans

Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice

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