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Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele
BACKGROUND: Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765906/ https://www.ncbi.nlm.nih.gov/pubmed/23957944 http://dx.doi.org/10.1186/1742-2094-10-102 |
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author | Dhungana, Hiramani Rolova, Taisia Savchenko, Ekaterina Wojciechowski, Sara Savolainen, Kaisa Ruotsalainen, Anna-Kaisa Sullivan, Patrick M Koistinaho, Jari Malm, Tarja |
author_facet | Dhungana, Hiramani Rolova, Taisia Savchenko, Ekaterina Wojciechowski, Sara Savolainen, Kaisa Ruotsalainen, Anna-Kaisa Sullivan, Patrick M Koistinaho, Jari Malm, Tarja |
author_sort | Dhungana, Hiramani |
collection | PubMed |
description | BACKGROUND: Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age are known to contribute to increased risk of cerebrovascular diseases. Clinical and preclinical studies have shown that the E4 allele of human apolipoprotein (ApoE4) is linked to poorer outcome in various conditions of brain injury and neurodegeneration, including cerebral ischemia. Since ApoE is a known regulator of lipid homeostasis, we studied the impact of a high-cholesterol diet in aged mice in the context of relevant human ApoE isoforms on the outcome of focal brain ischemia. METHODS: Aged mice expressing human E3 and E4 isoforms of ApoE in C57BL/6J background and C57BL/6J mice fed on either a high-fat diet or a normal diet underwent permanent middle cerebral artery occlusion. The impact of a high-cholesterol diet was assessed by measuring the serum cholesterol level and the infarction volume was determined by magnetic resonance imaging. Sensorimotor deficits were assessed using an adhesive removal test and the findings were correlated with inflammatory markers. RESULTS: We show that expression of human ApoE4 renders aged mice fed with a western-type diet more susceptible to sensorimotor deficits upon stroke. These deficits are not associated with atherosclerosis but are accompanied with altered astroglial activation, neurogenesis, cyclooxygenase-2 immunoreactivity and increased plasma IL-6. CONCLUSIONS: Our results support the hypothesis that ApoE alleles modify the inflammatory responses in the brain and the periphery, thus contributing to altered functional outcome following stroke. |
format | Online Article Text |
id | pubmed-3765906 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-37659062013-09-08 Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele Dhungana, Hiramani Rolova, Taisia Savchenko, Ekaterina Wojciechowski, Sara Savolainen, Kaisa Ruotsalainen, Anna-Kaisa Sullivan, Patrick M Koistinaho, Jari Malm, Tarja J Neuroinflammation Research BACKGROUND: Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age are known to contribute to increased risk of cerebrovascular diseases. Clinical and preclinical studies have shown that the E4 allele of human apolipoprotein (ApoE4) is linked to poorer outcome in various conditions of brain injury and neurodegeneration, including cerebral ischemia. Since ApoE is a known regulator of lipid homeostasis, we studied the impact of a high-cholesterol diet in aged mice in the context of relevant human ApoE isoforms on the outcome of focal brain ischemia. METHODS: Aged mice expressing human E3 and E4 isoforms of ApoE in C57BL/6J background and C57BL/6J mice fed on either a high-fat diet or a normal diet underwent permanent middle cerebral artery occlusion. The impact of a high-cholesterol diet was assessed by measuring the serum cholesterol level and the infarction volume was determined by magnetic resonance imaging. Sensorimotor deficits were assessed using an adhesive removal test and the findings were correlated with inflammatory markers. RESULTS: We show that expression of human ApoE4 renders aged mice fed with a western-type diet more susceptible to sensorimotor deficits upon stroke. These deficits are not associated with atherosclerosis but are accompanied with altered astroglial activation, neurogenesis, cyclooxygenase-2 immunoreactivity and increased plasma IL-6. CONCLUSIONS: Our results support the hypothesis that ApoE alleles modify the inflammatory responses in the brain and the periphery, thus contributing to altered functional outcome following stroke. BioMed Central 2013-08-20 /pmc/articles/PMC3765906/ /pubmed/23957944 http://dx.doi.org/10.1186/1742-2094-10-102 Text en Copyright © 2013 Dhungana et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Dhungana, Hiramani Rolova, Taisia Savchenko, Ekaterina Wojciechowski, Sara Savolainen, Kaisa Ruotsalainen, Anna-Kaisa Sullivan, Patrick M Koistinaho, Jari Malm, Tarja Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele |
title | Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele |
title_full | Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele |
title_fullStr | Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele |
title_full_unstemmed | Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele |
title_short | Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele |
title_sort | western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein e4 allele |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765906/ https://www.ncbi.nlm.nih.gov/pubmed/23957944 http://dx.doi.org/10.1186/1742-2094-10-102 |
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