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Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury

BACKGROUND: Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models sugg...

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Autores principales: Farr, Susan A., Cuzzocrea, Salvatore, Esposito, Emanuela, Campolo, Michela, Niehoff, Michael L., Doyle, Timothy M., Salvemini, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659122/
https://www.ncbi.nlm.nih.gov/pubmed/33183330
http://dx.doi.org/10.1186/s12974-020-02009-7
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author Farr, Susan A.
Cuzzocrea, Salvatore
Esposito, Emanuela
Campolo, Michela
Niehoff, Michael L.
Doyle, Timothy M.
Salvemini, Daniela
author_facet Farr, Susan A.
Cuzzocrea, Salvatore
Esposito, Emanuela
Campolo, Michela
Niehoff, Michael L.
Doyle, Timothy M.
Salvemini, Daniela
author_sort Farr, Susan A.
collection PubMed
description BACKGROUND: Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A(3) adenosine receptor (A(3)AR) can provide antiinflammatory and neuroprotective effects. However, the role of A(3)AR in TBI has not been investigated. METHODS: Using the selective A(3)AR agonist, MRS5980, we evaluated the effects of A(3)AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. RESULTS: When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4(+) and CD8(+) T cell influx. Moreover, when measured 4–5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. CONCLUSION: Our results provide support for the beneficial effects of small molecule A(3)AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.
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spelling pubmed-76591222020-11-13 Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury Farr, Susan A. Cuzzocrea, Salvatore Esposito, Emanuela Campolo, Michela Niehoff, Michael L. Doyle, Timothy M. Salvemini, Daniela J Neuroinflammation Research BACKGROUND: Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A(3) adenosine receptor (A(3)AR) can provide antiinflammatory and neuroprotective effects. However, the role of A(3)AR in TBI has not been investigated. METHODS: Using the selective A(3)AR agonist, MRS5980, we evaluated the effects of A(3)AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. RESULTS: When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4(+) and CD8(+) T cell influx. Moreover, when measured 4–5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. CONCLUSION: Our results provide support for the beneficial effects of small molecule A(3)AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI. BioMed Central 2020-11-12 /pmc/articles/PMC7659122/ /pubmed/33183330 http://dx.doi.org/10.1186/s12974-020-02009-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Farr, Susan A.
Cuzzocrea, Salvatore
Esposito, Emanuela
Campolo, Michela
Niehoff, Michael L.
Doyle, Timothy M.
Salvemini, Daniela
Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
title Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
title_full Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
title_fullStr Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
title_full_unstemmed Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
title_short Adenosine A(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
title_sort adenosine a(3) receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659122/
https://www.ncbi.nlm.nih.gov/pubmed/33183330
http://dx.doi.org/10.1186/s12974-020-02009-7
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