Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases
Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this...
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| Format: | Article |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2020.00090/full |
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| author | Adam Armada-Moreira Adam Armada-Moreira Adam Armada-Moreira Joana I. Gomes Joana I. Gomes Carolina Campos Pina Carolina Campos Pina Oksana K. Savchak Oksana K. Savchak Joana Gonçalves-Ribeiro Joana Gonçalves-Ribeiro Nádia Rei Nádia Rei Sara Pinto Sara Pinto Tatiana P. Morais Robertta Silva Martins Filipa F. Ribeiro Filipa F. Ribeiro Ana M. Sebastião Ana M. Sebastião Vincenzo Crunelli Vincenzo Crunelli Sandra H. Vaz Sandra H. Vaz |
| author_facet | Adam Armada-Moreira Adam Armada-Moreira Adam Armada-Moreira Joana I. Gomes Joana I. Gomes Carolina Campos Pina Carolina Campos Pina Oksana K. Savchak Oksana K. Savchak Joana Gonçalves-Ribeiro Joana Gonçalves-Ribeiro Nádia Rei Nádia Rei Sara Pinto Sara Pinto Tatiana P. Morais Robertta Silva Martins Filipa F. Ribeiro Filipa F. Ribeiro Ana M. Sebastião Ana M. Sebastião Vincenzo Crunelli Vincenzo Crunelli Sandra H. Vaz Sandra H. Vaz |
| author_sort | Adam Armada-Moreira |
| collection | DOAJ |
| description | Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease. |
| first_indexed | 2024-12-21T10:48:14Z |
| format | Article |
| id | doaj.art-57e1911ba2a4443e9afa0e7b04684a6c |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-21T10:48:14Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-57e1911ba2a4443e9afa0e7b04684a6c2022-12-21T19:06:44ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-04-011410.3389/fncel.2020.00090521326Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative DiseasesAdam Armada-Moreira0Adam Armada-Moreira1Adam Armada-Moreira2Joana I. Gomes3Joana I. Gomes4Carolina Campos Pina5Carolina Campos Pina6Oksana K. Savchak7Oksana K. Savchak8Joana Gonçalves-Ribeiro9Joana Gonçalves-Ribeiro10Nádia Rei11Nádia Rei12Sara Pinto13Sara Pinto14Tatiana P. Morais15Robertta Silva Martins16Filipa F. Ribeiro17Filipa F. Ribeiro18Ana M. Sebastião19Ana M. Sebastião20Vincenzo Crunelli21Vincenzo Crunelli22Sandra H. Vaz23Sandra H. Vaz24Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInterdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, DenmarkInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalNeuroscience Division, School of Bioscience, Cardiff University, Cardiff, United KingdomLaboratório de Neurofarmacologia, Instituto Biomédico, Universidade Federal Fluminense, Niterói, BrazilInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalNeuroscience Division, School of Bioscience, Cardiff University, Cardiff, United KingdomDepartment of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, MaltaInstituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, PortugalExcitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.https://www.frontiersin.org/article/10.3389/fncel.2020.00090/fullexcitotoxicityastrocytesNMDA receptorscalcium signalingneurodegenerative diseasesoxidative stress |
| spellingShingle | Adam Armada-Moreira Adam Armada-Moreira Adam Armada-Moreira Joana I. Gomes Joana I. Gomes Carolina Campos Pina Carolina Campos Pina Oksana K. Savchak Oksana K. Savchak Joana Gonçalves-Ribeiro Joana Gonçalves-Ribeiro Nádia Rei Nádia Rei Sara Pinto Sara Pinto Tatiana P. Morais Robertta Silva Martins Filipa F. Ribeiro Filipa F. Ribeiro Ana M. Sebastião Ana M. Sebastião Vincenzo Crunelli Vincenzo Crunelli Sandra H. Vaz Sandra H. Vaz Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases Frontiers in Cellular Neuroscience excitotoxicity astrocytes NMDA receptors calcium signaling neurodegenerative diseases oxidative stress |
| title | Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases |
| title_full | Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases |
| title_fullStr | Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases |
| title_full_unstemmed | Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases |
| title_short | Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases |
| title_sort | going the extra synaptic mile excitotoxicity as the road toward neurodegenerative diseases |
| topic | excitotoxicity astrocytes NMDA receptors calcium signaling neurodegenerative diseases oxidative stress |
| url | https://www.frontiersin.org/article/10.3389/fncel.2020.00090/full |
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