Mazzone, G.L.; Veeraraghavan, P.; Gonzalez-Inchauspe, C.; Nistri, A.; Uchitel, O.D."ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury" (2017) Neuroscience. 343:398-410
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In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. The present goal was to enquire if ASIC channels modulated KA damage in relation to locomotor network function and cell death. Mouse spinal cord slices were treated with KA (0.01 or 0.1 mM) for 1 h, and then washed out for 24 h prior to analysis. RT-PCR results showed that KA (at 0.01 mM concentration that is near-threshold for damage) increased mRNA expression of ASIC1a, ASIC1b, ASIC2 and ASIC3, an effect reversed by the ASIC inhibitor 4′,6-diamidino-2-phenylindole (DAPI). A KA neurotoxic dose (0.1 mM) reduced ASIC1a and ASIC2 expression. Cell viability assays demonstrated KA-induced large damage in spinal slices from mice with ASIC1a gene ablation. Likewise, immunohistochemistry indicated significant neuronal loss when KA was followed by the ASIC inhibitors DAPI or amiloride. Electrophysiological recording from ventral roots of isolated spinal cords showed that alternating oscillatory cycles were slowed down by 0.01 mM KA, and intensely inhibited by subsequently applied DAPI or amiloride. Our data suggest that early rise in ASIC expression and function counteracted deleterious effects on spinal networks by raising the excitotoxicity threshold, a result with potential implications for improving neuroprotection. © 2016 IBRO


Documento: Artículo
Título:ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury
Autor:Mazzone, G.L.; Veeraraghavan, P.; Gonzalez-Inchauspe, C.; Nistri, A.; Uchitel, O.D.
Filiación:Laboratorios de Investigación aplicada en Neurociencias (LIAN) – Fundación para la Lucha conntra las Enfermedades Neurológicas de la Infancia (FLENI), CONICET, Buenos Aires, Argentina
Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy
Instituto de Fisiología, Biología molecular y Neurociencias, CONICET, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Spinal Person Injury Neurorehabilitation Applied Laboratory (SPINAL), Istituto di Medicina Fisica e Riabilitazione, Udine, Italy
Palabras clave:acid sensing ion channels (ASICs); fictive locomotion; kainic acid; neuroprotection; pH; spinal cord injury; 4',6 diamidino 2 phenylindole; acid sensing ion channel; acid sensing ion channel 1a; acid sensing ion channel 1b; acid sensing ion channel 2; acid sensing ion channel 3; kainic acid; unclassified drug; acid sensing ion channel; acid sensing ion channel blocking agent; glutamic acid; indole derivative; kainic acid; messenger RNA; proton; animal cell; animal experiment; animal model; animal tissue; Article; cell counting; cell death; cell viability assay; concentration response; controlled study; excitotoxicity; gene expression; immunohistochemistry; mouse; nerve cell; nerve cell network; nervous system electrophysiology; neuroprotection; neurotoxicity; newborn; nonhuman; oscillatory potential; pH measurement; priority journal; protein expression; reverse transcription polymerase chain reaction; spinal cord injury; staining; animal; cell death; cell survival; disease model; dose response; drug effects; genetics; glia; metabolism; nerve cell; pathology; physiology; spinal cord; spinal cord injury; synaptic transmission; tissue culture technique; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; Animals; Cell Death; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Glutamic Acid; Indoles; Kainic Acid; Mice; Neuroglia; Neurons; Protons; RNA, Messenger; Spinal Cord; Spinal Cord Injuries; Synaptic Transmission; Tissue Culture Techniques
Página de inicio:398
Página de fin:410
Título revista:Neuroscience
Título revista abreviado:Neuroscience
CAS:4',6 diamidino 2 phenylindole, 47165-04-8; kainic acid, 487-79-6; glutamic acid, 11070-68-1, 138-15-8, 56-86-0, 6899-05-4; proton, 12408-02-5, 12586-59-3; Acid Sensing Ion Channel Blockers; Acid Sensing Ion Channels; DAPI; Glutamic Acid; Indoles; Kainic Acid; Protons; RNA, Messenger


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---------- APA ----------
Mazzone, G.L., Veeraraghavan, P., Gonzalez-Inchauspe, C., Nistri, A. & Uchitel, O.D. (2017) . ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury. Neuroscience, 343, 398-410.
---------- CHICAGO ----------
Mazzone, G.L., Veeraraghavan, P., Gonzalez-Inchauspe, C., Nistri, A., Uchitel, O.D. "ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury" . Neuroscience 343 (2017) : 398-410.
---------- MLA ----------
Mazzone, G.L., Veeraraghavan, P., Gonzalez-Inchauspe, C., Nistri, A., Uchitel, O.D. "ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury" . Neuroscience, vol. 343, 2017, pp. 398-410.
---------- VANCOUVER ----------
Mazzone, G.L., Veeraraghavan, P., Gonzalez-Inchauspe, C., Nistri, A., Uchitel, O.D. ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury. Neuroscience. 2017;343:398-410.