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Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats

PURPOSE: Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer’s disease (AD) compatible with the inflammation hypothesis of ageing (“inflammaging” state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflam...

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Autores principales: Wrona, Danuta, Majkutewicz, Irena, Świątek, Grzegorz, Dunacka, Joanna, Grembecka, Beata, Glac, Wojciech
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749052/
https://www.ncbi.nlm.nih.gov/pubmed/35027835
http://dx.doi.org/10.2147/JIR.S342280
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author Wrona, Danuta
Majkutewicz, Irena
Świątek, Grzegorz
Dunacka, Joanna
Grembecka, Beata
Glac, Wojciech
author_facet Wrona, Danuta
Majkutewicz, Irena
Świątek, Grzegorz
Dunacka, Joanna
Grembecka, Beata
Glac, Wojciech
author_sort Wrona, Danuta
collection PubMed
description PURPOSE: Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer’s disease (AD) compatible with the inflammation hypothesis of ageing (“inflammaging” state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflammatory and neuroprotective effects in the brain along with improvement in cognitive functions in rats with the ICV-STZ-induced model of AD. To evaluate whether DMF reduces neuroinflammation based on the peripheral inflammatory response inhibition, we determined peripheral inflammatory mediators in young and aged rats with the ICV-STZ-induced AD pathology following DMF therapy. MATERIALS AND METHODS: Young (4-month-old) and aged (22-month-old) rats were fed with 0.4% DMF rat chow for 21 consecutive days after ICV-STZ (3 mg/ventricle) injections. After behavioral testing, blood and spleens were collected to determine the numbers of leukocytes (WBC), lymphocytes and their subpopulations, haematological parameters, the concanavalin (Con)-A-induced production and plasma concentration of interferon (IFN)-γ, interleukin (IL)-6, IL-10 and corticosterone (COR). RESULTS: Age-dependent anti-inflammatory effect of the DMF treatment in rats with ICV-STZ injections manifested as decreased peripheral WBC and lymphocyte numbers, including TCD3(+)CD4(+)CD8(−), TCD3(+)CD4(−)CD8(+), B (CD45RA(+)) and NK (161a(+)), in aged rats. Furthermore, DMF lowered the blood and spleen lymphocyte production of pro-inflammatory IFN-γ and IL-6 in young and aged rats, whereas it enhanced the plasma level of anti-inflammatory IL-10 and lymphocyte’s ability to produce it in aged rats only. In parallel to changes in peripheral WBC numbers in the model of AD, DMF decreased the red blood cell number, haemoglobin concentration, haematocrit and mean platelet volume in aged, but not young, rats. In contrast to controls, DMF did not influence the COR response in STZ groups. CONCLUSION: Besides preventing neuroinflammation, DMF acts on the pro-/anti-inflammatory balance in the periphery and causes an anti-inflammatory shift in T lymphocytes which could contribute to DMF’s therapeutic effects in the ICV-STZ-induced model of AD, in particular, in aged rats.
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spelling pubmed-87490522022-01-12 Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats Wrona, Danuta Majkutewicz, Irena Świątek, Grzegorz Dunacka, Joanna Grembecka, Beata Glac, Wojciech J Inflamm Res Original Research PURPOSE: Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer’s disease (AD) compatible with the inflammation hypothesis of ageing (“inflammaging” state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflammatory and neuroprotective effects in the brain along with improvement in cognitive functions in rats with the ICV-STZ-induced model of AD. To evaluate whether DMF reduces neuroinflammation based on the peripheral inflammatory response inhibition, we determined peripheral inflammatory mediators in young and aged rats with the ICV-STZ-induced AD pathology following DMF therapy. MATERIALS AND METHODS: Young (4-month-old) and aged (22-month-old) rats were fed with 0.4% DMF rat chow for 21 consecutive days after ICV-STZ (3 mg/ventricle) injections. After behavioral testing, blood and spleens were collected to determine the numbers of leukocytes (WBC), lymphocytes and their subpopulations, haematological parameters, the concanavalin (Con)-A-induced production and plasma concentration of interferon (IFN)-γ, interleukin (IL)-6, IL-10 and corticosterone (COR). RESULTS: Age-dependent anti-inflammatory effect of the DMF treatment in rats with ICV-STZ injections manifested as decreased peripheral WBC and lymphocyte numbers, including TCD3(+)CD4(+)CD8(−), TCD3(+)CD4(−)CD8(+), B (CD45RA(+)) and NK (161a(+)), in aged rats. Furthermore, DMF lowered the blood and spleen lymphocyte production of pro-inflammatory IFN-γ and IL-6 in young and aged rats, whereas it enhanced the plasma level of anti-inflammatory IL-10 and lymphocyte’s ability to produce it in aged rats only. In parallel to changes in peripheral WBC numbers in the model of AD, DMF decreased the red blood cell number, haemoglobin concentration, haematocrit and mean platelet volume in aged, but not young, rats. In contrast to controls, DMF did not influence the COR response in STZ groups. CONCLUSION: Besides preventing neuroinflammation, DMF acts on the pro-/anti-inflammatory balance in the periphery and causes an anti-inflammatory shift in T lymphocytes which could contribute to DMF’s therapeutic effects in the ICV-STZ-induced model of AD, in particular, in aged rats. Dove 2022-01-06 /pmc/articles/PMC8749052/ /pubmed/35027835 http://dx.doi.org/10.2147/JIR.S342280 Text en © 2022 Wrona et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Wrona, Danuta
Majkutewicz, Irena
Świątek, Grzegorz
Dunacka, Joanna
Grembecka, Beata
Glac, Wojciech
Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats
title Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats
title_full Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats
title_fullStr Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats
title_full_unstemmed Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats
title_short Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats
title_sort dimethyl fumarate as the peripheral blood inflammatory mediators inhibitor in prevention of streptozotocin-induced neuroinflammation in aged rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749052/
https://www.ncbi.nlm.nih.gov/pubmed/35027835
http://dx.doi.org/10.2147/JIR.S342280
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