title: Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental Wernicke's encephalopathy.
abstract: Recent clinical trials suggest that patients with myelofibrosis can develop Wernicke's encephalopathy (WE) when treated with fedratinib, a specific Janus kinase-2 (JAK-2) inhibitor. To investigate this issue, we have examined (1) if fedratinib can produce or alter the course of this disorder, (2) its effects on thiamine-dependent enzyme activity and thiamine status, and (3) its influence on the uptake of thiamine. Animals administered fedratinib for 28days at a comparable dose used to treat human cases of myelofibrosis showed no evidence of clinical signs of thiamine deficiency (TD). Rats treated with a combination of fedratinib and TD exhibited no neurological differences in their progress to the symptomatic stage when compared to thiamine-deficient animals only. Treatment with the JAK-2 inhibitor did not compromise erythrocyte transketolase activity, and thiamine status was not affected in a major way unlike animals with TD. In addition, treatment of cultured astrocytes with fedratinib did not diminish the uptake of thiamine into these cells. Our findings suggest that treatment with fedratinib does not lead to or alter the progress of TD, and do not support the notion that administration of this JAK-2 inhibitor directly results in the development of WE due to inhibition of thiamine transport. Known adverse effects of fedratinib involving compromised gastrointestinal function may be an important indirect contributing factor to previously reported cases of WE in patients with myelofibrosis.
authors.affiliation: Department of Medicine, University of Montreal, Montreal, QC, Canada; Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address: alan.stewart.hazell@umontreal.ca.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Hazell
authors.affiliation: Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Szeifoul
authors.initials: S
authors.lastname: Afadlal
authors.affiliation: Department of Pathology, University of California, San Diego, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
authors.affiliation: Department of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Azar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D011759:Pyrrolidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013831:Thiamine / Q000097:blood; D013832:Thiamine Deficiency / Q000097:blood / Q000139:chemically induced*; D014899:Wernicke Encephalopathy / Q000139:chemically induced*; D000096926:Benzenesulfonamides
chemical_list: D053614:Janus Kinase 2; D011759:Pyrrolidines; D013449:Sulfonamides; D013831:Thiamine; C528327:fedratinib; D000096926:Benzenesulfonamides
keywords: Astrocyte; Excitotoxicity; Myelofibrosis; Neurodegeneration; Thiamine deficiency; Vitamin B1