Intracellular zinc is a critical intermediate in the excitotoxic cascade
Excessive and sustained exposure to glutamate leads to injurious elevations of cytosolic calcium ([Ca2+]i), generation of reactive oxygen and nitrogen species (ROS, RNS), mitochondrial failure, mobilization of intracellular zinc ([Zn2+]i), and, ultimately, neuronal death. The relative contribution a...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-09-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115001576 |
| _version_ | 1818728781830946816 |
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| author | Alberto Granzotto Stefano L. Sensi |
| author_facet | Alberto Granzotto Stefano L. Sensi |
| author_sort | Alberto Granzotto |
| collection | DOAJ |
| description | Excessive and sustained exposure to glutamate leads to injurious elevations of cytosolic calcium ([Ca2+]i), generation of reactive oxygen and nitrogen species (ROS, RNS), mitochondrial failure, mobilization of intracellular zinc ([Zn2+]i), and, ultimately, neuronal death. The relative contribution and temporal dynamics of the activation of these processes to promote the full development of excitotoxicity are still not completely understood. In this study, we exploited the unique features of nNOS positive neurons [nNOS (+)], a striatal subpopulation that is constitutively spared from NMDAR-dependent insults, and dissected NMDAR-driven [Ca2+]i, [Zn2+]i, ROS, and mitochondrial changes occurring in these neurons and the overall population of nNOS (−) striatal neurons. Comparing the two populations and employing pharmacological, biochemical, and single-cell imaging techniques, we show that [Zn2+]i mobilization acts as a critical intermediate in the cascade that links NMDAR-mediated ROS overproduction, mitochondrial failure, and [Ca2+]i deregulation to the production of neuronal damage. Results of this study may also provide the rationale for aiming at therapeutic agents that favor Zn2+ homeostasis for the treatment of acute or chronic neurological conditions associated with excitotoxicity. |
| first_indexed | 2024-12-17T22:35:27Z |
| format | Article |
| id | doaj.art-95d9cc00b3e94f49af1eb857a2e39848 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T22:35:27Z |
| publishDate | 2015-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-95d9cc00b3e94f49af1eb857a2e398482022-12-21T21:30:06ZengElsevierNeurobiology of Disease1095-953X2015-09-01812537Intracellular zinc is a critical intermediate in the excitotoxic cascadeAlberto Granzotto0Stefano L. Sensi1Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), Chieti, Italy; Department of Neuroscience and Imaging, University “G. d'Annunzio”, Chieti, ItalyMolecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), Chieti, Italy; Department of Neuroscience and Imaging, University “G. d'Annunzio”, Chieti, Italy; Departments of Neurology and Pharmacology, University of California-Irvine, Irvine, CA, USA; Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA; Corresponding author at: Ce.S.I. — Center of Excellence on Aging, Via Luigi Polacchi, 11, 66100, Chieti (CH), Italy. Fax: +39 0871541542.Excessive and sustained exposure to glutamate leads to injurious elevations of cytosolic calcium ([Ca2+]i), generation of reactive oxygen and nitrogen species (ROS, RNS), mitochondrial failure, mobilization of intracellular zinc ([Zn2+]i), and, ultimately, neuronal death. The relative contribution and temporal dynamics of the activation of these processes to promote the full development of excitotoxicity are still not completely understood. In this study, we exploited the unique features of nNOS positive neurons [nNOS (+)], a striatal subpopulation that is constitutively spared from NMDAR-dependent insults, and dissected NMDAR-driven [Ca2+]i, [Zn2+]i, ROS, and mitochondrial changes occurring in these neurons and the overall population of nNOS (−) striatal neurons. Comparing the two populations and employing pharmacological, biochemical, and single-cell imaging techniques, we show that [Zn2+]i mobilization acts as a critical intermediate in the cascade that links NMDAR-mediated ROS overproduction, mitochondrial failure, and [Ca2+]i deregulation to the production of neuronal damage. Results of this study may also provide the rationale for aiming at therapeutic agents that favor Zn2+ homeostasis for the treatment of acute or chronic neurological conditions associated with excitotoxicity.http://www.sciencedirect.com/science/article/pii/S0969996115001576CalciumGlutamateNeuronal deathMitochondriaOxidative stressnNOS |
| spellingShingle | Alberto Granzotto Stefano L. Sensi Intracellular zinc is a critical intermediate in the excitotoxic cascade Neurobiology of Disease Calcium Glutamate Neuronal death Mitochondria Oxidative stress nNOS |
| title | Intracellular zinc is a critical intermediate in the excitotoxic cascade |
| title_full | Intracellular zinc is a critical intermediate in the excitotoxic cascade |
| title_fullStr | Intracellular zinc is a critical intermediate in the excitotoxic cascade |
| title_full_unstemmed | Intracellular zinc is a critical intermediate in the excitotoxic cascade |
| title_short | Intracellular zinc is a critical intermediate in the excitotoxic cascade |
| title_sort | intracellular zinc is a critical intermediate in the excitotoxic cascade |
| topic | Calcium Glutamate Neuronal death Mitochondria Oxidative stress nNOS |
| url | http://www.sciencedirect.com/science/article/pii/S0969996115001576 |
| work_keys_str_mv | AT albertogranzotto intracellularzincisacriticalintermediateintheexcitotoxiccascade AT stefanolsensi intracellularzincisacriticalintermediateintheexcitotoxiccascade |