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Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease
Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialys...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520534/ https://www.ncbi.nlm.nih.gov/pubmed/34657122 http://dx.doi.org/10.1038/s41420-021-00685-9 |
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author | Natale, Giuseppina Calabrese, Valeria Marino, Gioia Campanelli, Federica Urciuolo, Federica de Iure, Antonio Ghiglieri, Veronica Calabresi, Paolo Bossola, Maurizio Picconi, Barbara |
author_facet | Natale, Giuseppina Calabrese, Valeria Marino, Gioia Campanelli, Federica Urciuolo, Federica de Iure, Antonio Ghiglieri, Veronica Calabresi, Paolo Bossola, Maurizio Picconi, Barbara |
author_sort | Natale, Giuseppina |
collection | PubMed |
description | Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient’s serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus. |
format | Online Article Text |
id | pubmed-8520534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85205342021-10-29 Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease Natale, Giuseppina Calabrese, Valeria Marino, Gioia Campanelli, Federica Urciuolo, Federica de Iure, Antonio Ghiglieri, Veronica Calabresi, Paolo Bossola, Maurizio Picconi, Barbara Cell Death Discov Article Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient’s serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus. Nature Publishing Group UK 2021-10-16 /pmc/articles/PMC8520534/ /pubmed/34657122 http://dx.doi.org/10.1038/s41420-021-00685-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Natale, Giuseppina Calabrese, Valeria Marino, Gioia Campanelli, Federica Urciuolo, Federica de Iure, Antonio Ghiglieri, Veronica Calabresi, Paolo Bossola, Maurizio Picconi, Barbara Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
title | Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
title_full | Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
title_fullStr | Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
title_full_unstemmed | Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
title_short | Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
title_sort | effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520534/ https://www.ncbi.nlm.nih.gov/pubmed/34657122 http://dx.doi.org/10.1038/s41420-021-00685-9 |
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