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...

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Autores principales:	Cellas A. Hayes, Brandon G. Ashmore, Akshaya Vijayasankar, Jessica P. Marshall, Nicole M. Ashpole
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	astrocytes endothelial cells neurotoxicity somatomedin C reactive oxygen species Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/2ae0723462b546f8a740f258594c5585
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spelling	oai:doaj.org-article:2ae0723462b546f8a740f258594c55852021-11-30T13:32:54ZInsulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit1663-436510.3389/fnagi.2021.751304https://doaj.org/article/2ae0723462b546f8a740f258594c55852021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnagi.2021.751304/fullhttps://doaj.org/toc/1663-4365The 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.Cellas A. HayesBrandon G. AshmoreAkshaya VijayasankarJessica P. MarshallNicole M. AshpoleNicole M. AshpoleFrontiers Media S.A.articleastrocytesendothelial cellsneurotoxicitysomatomedin Creactive oxygen speciesNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Aging Neuroscience, Vol 13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	astrocytes endothelial cells neurotoxicity somatomedin C reactive oxygen species Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	astrocytes endothelial cells neurotoxicity somatomedin C reactive oxygen species Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Cellas A. Hayes Brandon G. Ashmore Akshaya Vijayasankar Jessica P. Marshall Nicole M. Ashpole Nicole M. Ashpole Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit
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	article
author	Cellas A. Hayes Brandon G. Ashmore Akshaya Vijayasankar Jessica P. Marshall Nicole M. Ashpole Nicole M. Ashpole
author_facet	Cellas A. Hayes Brandon G. Ashmore Akshaya Vijayasankar Jessica P. Marshall Nicole M. Ashpole Nicole M. Ashpole
author_sort	Cellas A. Hayes
title	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_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_sort	insulin-like growth factor-1 differentially modulates glutamate-induced toxicity and stress in cells of the neurogliovascular unit
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2ae0723462b546f8a740f258594c5585
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Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

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