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Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit
The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular commu...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650493/ https://www.ncbi.nlm.nih.gov/pubmed/34887742 http://dx.doi.org/10.3389/fnagi.2021.751304 |
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author | Hayes, Cellas A. Ashmore, Brandon G. Vijayasankar, Akshaya Marshall, Jessica P. Ashpole, Nicole M. |
author_facet | Hayes, Cellas A. Ashmore, Brandon G. Vijayasankar, Akshaya Marshall, Jessica P. Ashpole, Nicole M. |
author_sort | Hayes, Cellas A. |
collection | PubMed |
description | The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit. |
format | Online Article Text |
id | pubmed-8650493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86504932021-12-08 Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit Hayes, Cellas A. Ashmore, Brandon G. Vijayasankar, Akshaya Marshall, Jessica P. Ashpole, Nicole M. Front Aging Neurosci Neuroscience The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit. Frontiers Media S.A. 2021-11-23 /pmc/articles/PMC8650493/ /pubmed/34887742 http://dx.doi.org/10.3389/fnagi.2021.751304 Text en Copyright © 2021 Hayes, Ashmore, Vijayasankar, Marshall and Ashpole. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Hayes, Cellas A. Ashmore, Brandon G. Vijayasankar, Akshaya Marshall, Jessica P. Ashpole, Nicole M. Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit |
title | Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit |
title_full | Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit |
title_fullStr | Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit |
title_full_unstemmed | Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit |
title_short | Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit |
title_sort | insulin-like growth factor-1 differentially modulates glutamate-induced toxicity and stress in cells of the neurogliovascular unit |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650493/ https://www.ncbi.nlm.nih.gov/pubmed/34887742 http://dx.doi.org/10.3389/fnagi.2021.751304 |
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