title: Brain endothelial dysfunction following pyrithiamine induced thiamine deficiency in the rat.
abstract: Prolonged vitamin B1(thiamine) deficiency can lead to neurological disorders such as Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome (WKS) in humans. These thiamine deficiency disorders have been attributed to vascular leakage, blood-brain barrier breakdown and neuronal loss in the diencephalon and brain stem. However, endothelial dysfunction following thiamine deficiency and its relationship to the phenomenon of neurodegeneration has not been clearly elucidated. The present study sought to begin to address this issue by evaluating vascular morphology and integrity in a pyrithiamine (PT)-induced rat model of thiamine deficiency. Adjacent brain sections were used to either assess vascular integrity through immunohistochemical localization of rat endothelial cell antigen (RECA-1) and endothelial brain barrier antigen (EBA-1) or neurodegeneration using the de Olmos cupric silver method. GFAP and CD11b immunolabeling was used to evaluate astrocytic and microglial/macrophagic changes. Extensive neurodegeneration occurred concomitant with both vascular damage (thinning and breakage) and microglial activation in the inferior olive, medial thalamic area, and medial geniculate nuclei of pyrithiamine treated rats. Likewise, glucose transporter-1 (Glut-1), which is mostly expressed in endothelial cells, was also severely decreased in this pyrithiamine induced thiamine deficient rat model. MRI scans of these animals prior to sacrifice show that the pyrithiamine induced thiamine deficient animals have abnormal T2relaxation values, which are commensurate with, and possibly predictive of, the neurodegeneration and/or endothelial dysfunction subsequently observed histologically in these same animals.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR-72079, USA. Electronic address: Sumit.Sarkar@FDA.hhs.gov.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR-72079, USA.
authors.forename: Serguei
authors.initials: S
authors.lastname: Liachenko
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR-72079, USA.
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR-72079, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bowyer
authors.affiliation: Office of Testing & Research, CDER/FDA, White Oak, MD-20993, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D000963:Antimetabolites / Q000633:toxicity*; D001253:Astrocytes / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000209:etiology; D011745:Pyrithiamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining; D013832:Thiamine Deficiency / Q000139:chemically induced* / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D000954:Antigens, Surface; D000963:Antimetabolites; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; C114781:endothelial barrier antigen, rat; D011745:Pyrithiamine
keywords: Astrocytes; Endothelial cells; Microglia; Neurodegeneration; Pyrithiamine