Cargando…

High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats

The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Spragu...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Junzhi, Betterton, Robert D., Williams, Erica I., Stanton, Joshua A., Reddell, Elizabeth S., Ogbonnaya, Chidinma E., Dorn, Emma, Davis, Thomas P., Lochhead, Jeffrey J., Ronaldson, Patrick T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144323/
https://www.ncbi.nlm.nih.gov/pubmed/35631535
http://dx.doi.org/10.3390/pharmaceutics14050949
_version_ 1784716020450066432
author Yang, Junzhi
Betterton, Robert D.
Williams, Erica I.
Stanton, Joshua A.
Reddell, Elizabeth S.
Ogbonnaya, Chidinma E.
Dorn, Emma
Davis, Thomas P.
Lochhead, Jeffrey J.
Ronaldson, Patrick T.
author_facet Yang, Junzhi
Betterton, Robert D.
Williams, Erica I.
Stanton, Joshua A.
Reddell, Elizabeth S.
Ogbonnaya, Chidinma E.
Dorn, Emma
Davis, Thomas P.
Lochhead, Jeffrey J.
Ronaldson, Patrick T.
author_sort Yang, Junzhi
collection PubMed
description The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [(14)C]sucrose and [(3)H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [(14)C]sucrose “leak” and brain [(3)H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products.
format Online
Article
Text
id pubmed-9144323
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91443232022-05-29 High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats Yang, Junzhi Betterton, Robert D. Williams, Erica I. Stanton, Joshua A. Reddell, Elizabeth S. Ogbonnaya, Chidinma E. Dorn, Emma Davis, Thomas P. Lochhead, Jeffrey J. Ronaldson, Patrick T. Pharmaceutics Article The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [(14)C]sucrose and [(3)H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [(14)C]sucrose “leak” and brain [(3)H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products. MDPI 2022-04-27 /pmc/articles/PMC9144323/ /pubmed/35631535 http://dx.doi.org/10.3390/pharmaceutics14050949 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Junzhi
Betterton, Robert D.
Williams, Erica I.
Stanton, Joshua A.
Reddell, Elizabeth S.
Ogbonnaya, Chidinma E.
Dorn, Emma
Davis, Thomas P.
Lochhead, Jeffrey J.
Ronaldson, Patrick T.
High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
title High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
title_full High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
title_fullStr High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
title_full_unstemmed High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
title_short High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats
title_sort high-dose acetaminophen alters the integrity of the blood–brain barrier and leads to increased cns uptake of codeine in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144323/
https://www.ncbi.nlm.nih.gov/pubmed/35631535
http://dx.doi.org/10.3390/pharmaceutics14050949
work_keys_str_mv AT yangjunzhi highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT bettertonrobertd highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT williamsericai highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT stantonjoshuaa highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT reddellelizabeths highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT ogbonnayachidinmae highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT dornemma highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT davisthomasp highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT lochheadjeffreyj highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats
AT ronaldsonpatrickt highdoseacetaminophenalterstheintegrityofthebloodbrainbarrierandleadstoincreasedcnsuptakeofcodeineinrats