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4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice

BACKGROUND: Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a...

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Autores principales: Rojas-Colón, Luis A., Dash, Pramod K., Morales-Vías, Fabiola A., Lebrón-Dávila, Madeline, Ferchmin, Pedro A., Redell, John B., Maldonado-Martínez, Geronimo, Vélez-Torres, Wanda I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054431/
https://www.ncbi.nlm.nih.gov/pubmed/33874954
http://dx.doi.org/10.1186/s12974-021-02136-9
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author Rojas-Colón, Luis A.
Dash, Pramod K.
Morales-Vías, Fabiola A.
Lebrón-Dávila, Madeline
Ferchmin, Pedro A.
Redell, John B.
Maldonado-Martínez, Geronimo
Vélez-Torres, Wanda I.
author_facet Rojas-Colón, Luis A.
Dash, Pramod K.
Morales-Vías, Fabiola A.
Lebrón-Dávila, Madeline
Ferchmin, Pedro A.
Redell, John B.
Maldonado-Martínez, Geronimo
Vélez-Torres, Wanda I.
author_sort Rojas-Colón, Luis A.
collection PubMed
description BACKGROUND: Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. LPS injection into mice causes systemic inflammation, neuronal damage, and poor memory outcomes if the inflammation is not controlled. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. The purpose of this study is to determine whether 4R reduces the deleterious effects of LPS-induced neuroinflammation and whether the α7 receptor plays a role in mediating these beneficial effects. METHODS: Ex vivo population spike recordings were performed in C57BL/6J wild-type (WT) and alpha-7-knockout (α7KO) mouse hippocampal slices in the presence of 4R and nicotinic receptor inhibitors. For in vivo studies, WT and α7KO mice were injected with LPS for 2 h, followed by 4R or vehicle for 22 h. Analyses of IL-1β, TNF-α, STAT3, CREB, Akt1, and the long-term novel object recognition test (NORT) were performed for both genotypes. In addition, RNA sequencing and RT-qPCR analyses were carried out for 12 mRNAs related to neuroinflammation and their modification by 4R. RESULTS: 4R confers neuroprotection after NMDA-induced neurotoxicity in both WT and α7KO mice. Moreover, hippocampal TNF-α and IL-1β levels were decreased with 4R treatment following LPS exposure in both strains of mice. 4R restored LPS-induced cognitive decline in NORT. There was a significant increase in the phosphorylation of STAT3, CREB, and Akt1 with 4R treatment in the WT mouse hippocampus following LPS exposure. In α7KO mice, only pAkt levels were significantly elevated in the cortex. 4R significantly upregulated mRNA levels of ORM2, GDNF, and C3 following LPS exposure. These proteins are known to play a role in modulating microglial activation, neuronal survival, and memory. CONCLUSION: Our results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates STAT3, Akt1, and CREB phosphorylation; and upregulates the mRNA levels of ORM2, GDNF, and C3. These effects are independent of the α7 nicotinic receptor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02136-9.
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spelling pubmed-80544312021-04-20 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice Rojas-Colón, Luis A. Dash, Pramod K. Morales-Vías, Fabiola A. Lebrón-Dávila, Madeline Ferchmin, Pedro A. Redell, John B. Maldonado-Martínez, Geronimo Vélez-Torres, Wanda I. J Neuroinflammation Research BACKGROUND: Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation. LPS injection into mice causes systemic inflammation, neuronal damage, and poor memory outcomes if the inflammation is not controlled. Activation of the alpha-7 nicotinic receptor (α7) plays an anti-inflammatory role in the brain through vagal efferent nerve signaling. 4R-cembranoid (4R) is a natural compound that crosses the blood-brain barrier, induces neuronal survival, and has been shown to modulate the activity of nicotinic receptors. The purpose of this study is to determine whether 4R reduces the deleterious effects of LPS-induced neuroinflammation and whether the α7 receptor plays a role in mediating these beneficial effects. METHODS: Ex vivo population spike recordings were performed in C57BL/6J wild-type (WT) and alpha-7-knockout (α7KO) mouse hippocampal slices in the presence of 4R and nicotinic receptor inhibitors. For in vivo studies, WT and α7KO mice were injected with LPS for 2 h, followed by 4R or vehicle for 22 h. Analyses of IL-1β, TNF-α, STAT3, CREB, Akt1, and the long-term novel object recognition test (NORT) were performed for both genotypes. In addition, RNA sequencing and RT-qPCR analyses were carried out for 12 mRNAs related to neuroinflammation and their modification by 4R. RESULTS: 4R confers neuroprotection after NMDA-induced neurotoxicity in both WT and α7KO mice. Moreover, hippocampal TNF-α and IL-1β levels were decreased with 4R treatment following LPS exposure in both strains of mice. 4R restored LPS-induced cognitive decline in NORT. There was a significant increase in the phosphorylation of STAT3, CREB, and Akt1 with 4R treatment in the WT mouse hippocampus following LPS exposure. In α7KO mice, only pAkt levels were significantly elevated in the cortex. 4R significantly upregulated mRNA levels of ORM2, GDNF, and C3 following LPS exposure. These proteins are known to play a role in modulating microglial activation, neuronal survival, and memory. CONCLUSION: Our results indicate that 4R decreases the levels of pro-inflammatory cytokines; improves memory function; activates STAT3, Akt1, and CREB phosphorylation; and upregulates the mRNA levels of ORM2, GDNF, and C3. These effects are independent of the α7 nicotinic receptor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02136-9. BioMed Central 2021-04-19 /pmc/articles/PMC8054431/ /pubmed/33874954 http://dx.doi.org/10.1186/s12974-021-02136-9 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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
Rojas-Colón, Luis A.
Dash, Pramod K.
Morales-Vías, Fabiola A.
Lebrón-Dávila, Madeline
Ferchmin, Pedro A.
Redell, John B.
Maldonado-Martínez, Geronimo
Vélez-Torres, Wanda I.
4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice
title 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice
title_full 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice
title_fullStr 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice
title_full_unstemmed 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice
title_short 4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice
title_sort 4r-cembranoid confers neuroprotection against lps-induced hippocampal inflammation in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054431/
https://www.ncbi.nlm.nih.gov/pubmed/33874954
http://dx.doi.org/10.1186/s12974-021-02136-9
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