Multi-target novel neuroprotective compound ITH33/IQM9.21 inhibits calcium entry, calcium signals and exocytosis |
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Authors: | Maroto Marcos de Diego Antonio M G Albiñana Elisa Fernandez-Morales José C Caricati-Neto Afonso Jurkiewicz Aron Yáñez Matilde Rodriguez-Franco María Isabel Conde Santiago Arce Mariana P Hernández-Guijo Jesús M García Antonio G |
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Affiliation: | aInstituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;bDepartamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;cInstituto Sanitario de Investigación, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;dInstituto de Química Médica, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain;eDepartamento de Farmacología, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil;fDepartamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Spain |
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Abstract: | Compound ITH33/IQM9.21 (ITH/IQM) belongs to a new family of l-glutamic acid derivatives with antioxidant and neuroprotective properties on in vitro and in vivo models of stroke. Because neuronal damage after brain ischemia is tightly linked to excess Ca2+ entry and neuronal Ca2+ overload, we have investigated whether compound ITH/IQM antagonises the elevations of the cytosolic Ca2+ concentrations ([Ca2+]c) and the ensuing exocytotic responses triggered by depolarisation of bovine chromaffin cells. In fluo-4-loaded cell populations, ITH/IQM reduced the K+-evoked [Ca2+]c transients with an IC50 of 5.31 μM. At 10 μM, the compound decreased the amplitude and area of the Ca2+ transient elicited by challenging single fura-2-loaded cells with high K+, by 40% and 80%, respectively. This concentration also caused a blockade of K+-induced catecholamine release at the single-cell level (78%) and cell populations (55%). These effects are likely due to blockade of the whole-cell inward Ca2+ currents (IC50 = 6.52 μM). At 10 μM, ITH/IQM also inhibited the Ca2+-dependent outward K+ current, leaving untouched the voltage-dependent component of IK. The inward Na+ current was unaffected. Inhibition of depolarisation-elicited Ca2+ entry, [Ca2+]c elevation and exocytosis could contribute to the neuroprotective effects of ITH/IQM in vulnerable neurons undergoing depolarisation during brain ischemia. |
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Keywords: | Abbreviations: ITH, Instituto Teó filo Hernando IQM, Instituto de Quí mica Mé dica ITH33/IQM9.21, (N-Benzoyl-LGlu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex) oxalate salt BBB, Blood Brain Barrier [Ca2+]c, cytosolic calcium concentrations AD, Alzheimer's disease ICa, whole-cell inward calcium currents INa, whole-cell inward sodium current IK(Ca), Ca2+-dependent K+ currents Aβ, amyloid beta ALS, Amyotrophic Lateral Sclerosis mPTP, mitochondrial permeability transition pore PD, Parkinson's disease HD, Hungtinton's disease VDCC, voltage-dependent calcium channels SOD1, superoxide dismutase 1 AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor EDTA, ethylenediaminetetraacetic acid EGTA, [ethylenebis(oxyethylenenitrilo)] tetraacetic acid HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid DMEM, Dulbecco's modified Eagle's medium |
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