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Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats

PURPOSE: Cadmium is a heavy metal and environmental toxicant known to act on the central cardiovascular regulatory mechanisms, and one of its brain targets is the rostral ventrolateral medulla (RVLM), a brainstem site that maintains blood pressure and sympathetic vasomotor tone. The present study as...

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Autores principales: Tsai, Ching-Yi, Fang, Chi, Wu, Jacqueline C C, Wu, Chiung-Ju, Dai, Kuang-Yu, Chen, Shu-Mi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364915/
https://www.ncbi.nlm.nih.gov/pubmed/34408468
http://dx.doi.org/10.2147/JIR.S325528
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author Tsai, Ching-Yi
Fang, Chi
Wu, Jacqueline C C
Wu, Chiung-Ju
Dai, Kuang-Yu
Chen, Shu-Mi
author_facet Tsai, Ching-Yi
Fang, Chi
Wu, Jacqueline C C
Wu, Chiung-Ju
Dai, Kuang-Yu
Chen, Shu-Mi
author_sort Tsai, Ching-Yi
collection PubMed
description PURPOSE: Cadmium is a heavy metal and environmental toxicant known to act on the central cardiovascular regulatory mechanisms, and one of its brain targets is the rostral ventrolateral medulla (RVLM), a brainstem site that maintains blood pressure and sympathetic vasomotor tone. The present study assessed the hypothesis that cadmium elicits cardiovascular dysregulation by inducing neuroinflammation and microglial activation, two potential cellular mechanisms, in RVLM. METHODS: Adult male Sprague–Dawley rats were used for measuring cardiovascular responses after intravenous administration of cadmium. We further conducted real-time PCR, immunofluorescence staining, in situ determination of mitochondrial superoxide, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay (ELISA) to identify cytokine and chemokine mRNA expression, microglia activation, superoxide production, and necrotic and apoptotic cell death in RVLM. RESULTS: We found animals maintained under propofol anesthesia, intravenous administration of cadmium acetate (4 mg/kg) resulted in an increase, followed by a rebound and a secondary decrease in spontaneous baroreflex-mediated sympathetic vasomotor tone, a progressive reduction in mean arterial pressure and heart rate, alongside augmentation of pro-inflammatory cytokine and chemokine in RVLM. All those cardiovascular and neuroinflammatory events were reversed by pretreatment with an anti-inflammatory drug, pentoxifylline (50 mg/kg, i.p.). There were also concurrent microglial activation, reactive oxygen species production, hypoxia, reduced blood flow, and necrotic and apoptotic cell death in RVLM. CONCLUSION: Based on these biochemical, pharmacological and morphological observations, we conclude that neuroinflammation and microglial activation at RVLM, and their downstream cellular mechanisms, causally underpin cadmium-induced cardiovascular dysregulation.
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spelling pubmed-83649152021-08-17 Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats Tsai, Ching-Yi Fang, Chi Wu, Jacqueline C C Wu, Chiung-Ju Dai, Kuang-Yu Chen, Shu-Mi J Inflamm Res Original Research PURPOSE: Cadmium is a heavy metal and environmental toxicant known to act on the central cardiovascular regulatory mechanisms, and one of its brain targets is the rostral ventrolateral medulla (RVLM), a brainstem site that maintains blood pressure and sympathetic vasomotor tone. The present study assessed the hypothesis that cadmium elicits cardiovascular dysregulation by inducing neuroinflammation and microglial activation, two potential cellular mechanisms, in RVLM. METHODS: Adult male Sprague–Dawley rats were used for measuring cardiovascular responses after intravenous administration of cadmium. We further conducted real-time PCR, immunofluorescence staining, in situ determination of mitochondrial superoxide, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay (ELISA) to identify cytokine and chemokine mRNA expression, microglia activation, superoxide production, and necrotic and apoptotic cell death in RVLM. RESULTS: We found animals maintained under propofol anesthesia, intravenous administration of cadmium acetate (4 mg/kg) resulted in an increase, followed by a rebound and a secondary decrease in spontaneous baroreflex-mediated sympathetic vasomotor tone, a progressive reduction in mean arterial pressure and heart rate, alongside augmentation of pro-inflammatory cytokine and chemokine in RVLM. All those cardiovascular and neuroinflammatory events were reversed by pretreatment with an anti-inflammatory drug, pentoxifylline (50 mg/kg, i.p.). There were also concurrent microglial activation, reactive oxygen species production, hypoxia, reduced blood flow, and necrotic and apoptotic cell death in RVLM. CONCLUSION: Based on these biochemical, pharmacological and morphological observations, we conclude that neuroinflammation and microglial activation at RVLM, and their downstream cellular mechanisms, causally underpin cadmium-induced cardiovascular dysregulation. Dove 2021-08-11 /pmc/articles/PMC8364915/ /pubmed/34408468 http://dx.doi.org/10.2147/JIR.S325528 Text en © 2021 Tsai 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
Tsai, Ching-Yi
Fang, Chi
Wu, Jacqueline C C
Wu, Chiung-Ju
Dai, Kuang-Yu
Chen, Shu-Mi
Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats
title Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats
title_full Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats
title_fullStr Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats
title_full_unstemmed Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats
title_short Neuroinflammation and Microglial Activation at Rostral Ventrolateral Medulla Underpin Cadmium-Induced Cardiovascular Dysregulation in Rats
title_sort neuroinflammation and microglial activation at rostral ventrolateral medulla underpin cadmium-induced cardiovascular dysregulation in rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364915/
https://www.ncbi.nlm.nih.gov/pubmed/34408468
http://dx.doi.org/10.2147/JIR.S325528
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