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Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats

Based on several lines of evidence, numerous investigators have suggested that acetaminophen exposure during early development can induce neurological disorders. We had previously postulated that acetaminophen exposure early in life, if combined with antioxidants that prevent accumulation of NAPQI,...

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Autores principales: Suda, Navneet, Cendejas Hernandez, Jasmine, Poulton, John, Jones, John P., Konsoula, Zacharoula, Smith, Caroline, Parker, William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232535/
https://www.ncbi.nlm.nih.gov/pubmed/34170958
http://dx.doi.org/10.1371/journal.pone.0253543
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author Suda, Navneet
Cendejas Hernandez, Jasmine
Poulton, John
Jones, John P.
Konsoula, Zacharoula
Smith, Caroline
Parker, William
author_facet Suda, Navneet
Cendejas Hernandez, Jasmine
Poulton, John
Jones, John P.
Konsoula, Zacharoula
Smith, Caroline
Parker, William
author_sort Suda, Navneet
collection PubMed
description Based on several lines of evidence, numerous investigators have suggested that acetaminophen exposure during early development can induce neurological disorders. We had previously postulated that acetaminophen exposure early in life, if combined with antioxidants that prevent accumulation of NAPQI, the toxic metabolite of acetaminophen, might be innocuous. In this study, we administered acetaminophen at or below the currently recommended therapeutic dose to male laboratory rat pups aged 4–10 days. The antioxidants cysteine and mannitol were included to prevent accumulation of NAPQI. In addition, animals were exposed to a cassette of common stress factors: an inflammatory diet, psychological stress, antibiotics, and mock infections using killed bacteria. At age 37–49 days, observation during introduction to a novel conspecific revealed increased rearing behavior, an asocial activity, in animals treated with acetaminophen plus antioxidants, regardless of their exposure to oxidative stress factors (2-way ANOVA; P < 0.0001). This observation would suggest that the initial hypothesis is incorrect, and that oxidative stress mediators do not entirely eliminate the effects of acetaminophen on neurodevelopment. This study provides additional cause for caution when considering the use of acetaminophen in the pediatric population, and provides evidence that the effects of acetaminophen on neurodevelopment need to be considered both in the presence and in the absence of oxidative stress.
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spelling pubmed-82325352021-07-07 Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats Suda, Navneet Cendejas Hernandez, Jasmine Poulton, John Jones, John P. Konsoula, Zacharoula Smith, Caroline Parker, William PLoS One Research Article Based on several lines of evidence, numerous investigators have suggested that acetaminophen exposure during early development can induce neurological disorders. We had previously postulated that acetaminophen exposure early in life, if combined with antioxidants that prevent accumulation of NAPQI, the toxic metabolite of acetaminophen, might be innocuous. In this study, we administered acetaminophen at or below the currently recommended therapeutic dose to male laboratory rat pups aged 4–10 days. The antioxidants cysteine and mannitol were included to prevent accumulation of NAPQI. In addition, animals were exposed to a cassette of common stress factors: an inflammatory diet, psychological stress, antibiotics, and mock infections using killed bacteria. At age 37–49 days, observation during introduction to a novel conspecific revealed increased rearing behavior, an asocial activity, in animals treated with acetaminophen plus antioxidants, regardless of their exposure to oxidative stress factors (2-way ANOVA; P < 0.0001). This observation would suggest that the initial hypothesis is incorrect, and that oxidative stress mediators do not entirely eliminate the effects of acetaminophen on neurodevelopment. This study provides additional cause for caution when considering the use of acetaminophen in the pediatric population, and provides evidence that the effects of acetaminophen on neurodevelopment need to be considered both in the presence and in the absence of oxidative stress. Public Library of Science 2021-06-25 /pmc/articles/PMC8232535/ /pubmed/34170958 http://dx.doi.org/10.1371/journal.pone.0253543 Text en © 2021 Suda et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Suda, Navneet
Cendejas Hernandez, Jasmine
Poulton, John
Jones, John P.
Konsoula, Zacharoula
Smith, Caroline
Parker, William
Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
title Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
title_full Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
title_fullStr Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
title_full_unstemmed Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
title_short Therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
title_sort therapeutic doses of acetaminophen with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232535/
https://www.ncbi.nlm.nih.gov/pubmed/34170958
http://dx.doi.org/10.1371/journal.pone.0253543
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