title: Prions efficiently cross the intestinal barrier after oral administration: Study of the bioavailability, and cellular and tissue distribution in vivo.
abstract: Natural forms of prion diseases frequently originate by oral (p.o.) infection. However, quantitative information on the gastro-intestinal (GI) absorption of prions (i.e. the bioavailability and subsequent biodistribution) is mostly unknown. The main goal of this study was to evaluate the fate of prions after oral administration, using highly purified radiolabeled PrP(Sc). The results showed a bi-phasic reduction of PrP(Sc) with time in the GI, except for the ileum and colon which showed sustained increases peaking at 3-6 hr, respectively. Plasma and whole blood (125)I-PrP(Sc) reached maximal levels by 30 min and 3 hr, respectively, and blood levels were constantly higher than plasma. Upon crossing the GI-tract (125)I-PrP(Sc) became associated to blood cells, suggesting that binding to cells decreased the biological clearance of the agent. Size-exclusion chromatography revealed that oligomeric (125)I-PrP(Sc) were transported from the intestinal tract, and protein misfolding cyclic amplification showed that PrP(Sc) in organs and blood retained the typical prion self-replicating ability. Pharmacokinetic analysis found the oral bioavailability of (125)I-PrP(Sc) to be 33.6%. Interestingly, (125)I-PrP(Sc) reached the brain in a quantity equivalent to the minimum amount needed to initiate prion disease. Our findings provide a comprehensive and quantitative study of the fate of prions upon oral infection.
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School at Houston, Texas, United States of America.
authors: Akihiko
authors: A
authors: Urayama
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School at Houston, Texas, United States of America.|Universidad de los Andes, Facultad de Medicina, 2200 San Carlos de Apoquindo Av., Las Condes, Santiago 7620001, Chile.
authors: Luis
authors: L
authors: Concha-Marambio
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School at Houston, Texas, United States of America.
authors: Uffaf
authors: U
authors: Khan
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School at Houston, Texas, United States of America.|Universidad de los Andes, Facultad de Medicina, 2200 San Carlos de Apoquindo Av., Las Condes, Santiago 7620001, Chile.
authors: Javiera
authors: J
authors: Bravo-Alegria
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School at Houston, Texas, United States of America.
authors: Vineetkumar
authors: V
authors: Kharat
authors: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Medical School at Houston, Texas, United States of America.|Universidad de los Andes, Facultad de Medicina, 2200 San Carlos de Apoquindo Av., Las Condes, Santiago 7620001, Chile.
authors: Claudio
authors: C
authors: Soto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D007457:Iodine Radioisotopes / Q000737:chemistry; D051379:Mice; D018620:PrPSc Proteins / Q000235:genetics* / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D017510:Protein Folding; D014018:Tissue Distribution / Q000235:genetics
chemical_list: D007457:Iodine Radioisotopes; D018620:PrPSc Proteins; D011328:Prions