title: Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice.
abstract: Alzheimer's disease (AD) is characterized by memory loss and the upregulation of pro-neuroinflammatory factors such as cRaf-1, cyclooxygenase-2 (Cox-2), and the nuclear factor kappa B (NF-kappaB), as well as a downregulation of protein kinase A (PKA) activity and the activation by phosphorylation of its downstream factor CREB. We investigated the effect of the anti-cancer cRaf-1 inhibitor, sorafenib tosylate (Nexavar), on the expression of these factors and on the cognitive performance of aged APPswe mice. We found that chronic treatment with sorafenib stimulated PKA and CREB phosphorylation and inhibited cRaf-1 and NF-kappaB in the brains of APPswe mice. NF-kappaB controls the expression of several genes related to AD pathology, including iNOS and Cox-(2)Concurrent with NF-kappaB inhibition, sorafenib treatment decreased the cerebral expression of Cox-2 and iNOS in APPswe mice. It has recently been observed that Cox-2 inhibition prevents cognitive impairment in a mouse model of AD and amyloid beta peptide (Abeta)-induced inhibition of long-term potentiation (LTP). Consistent with the idea that Cox-2 inhibition can improve cognitive abilities, we found that sorafenib restored working memory abilities in aged APPswe mice without reducing Abeta levels in the brain. These findings suggest that sorafenib reduced AD pathology by reducing neuroinflammation.
authors.affiliation: Bay Pines VA Healthcare System, 10,000 Bay Pines Boulevard, Building 23, Room 123, Bay Pines, FL 33744, USA. Valentina.Echeverria@va.gov
authors.forename: V
authors.initials: V
authors.lastname: Echeverria
authors.forename: S
authors.initials: S
authors.lastname: Burgess
authors.forename: J
authors.initials: J
authors.lastname: Gamble-George
authors.forename: R
authors.initials: R
authors.lastname: Zeitlin
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: C
authors.initials: C
authors.lastname: Cao
authors.forename: G W
authors.initials: GW
authors.lastname: Arendash
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008817:Mice, Mutant Strains; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018697:Nootropic Agents / Q000494:pharmacology*; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D052246:Cyclooxygenase 2 Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; C000606205:Nfkbia protein, mouse; D018697:Nootropic Agents; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases