title: Multi-target novel neuroprotective compound ITH33/IQM9.21 inhibits calcium entry, calcium signals and exocytosis.
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.
authors.affiliation: Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, and Instituto Sanitario de Investigación, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Maroto
authors.forename: Antonio M G
authors.initials: AM
authors.lastname: de Diego
authors.forename: Elisa
authors.initials: E
authors.lastname: Albiñana
authors.forename: José C
authors.initials: JC
authors.lastname: Fernandez-Morales
authors.forename: Afonso
authors.initials: A
authors.lastname: Caricati-Neto
authors.forename: Aron
authors.initials: A
authors.lastname: Jurkiewicz
authors.forename: Matilde
authors.initials: M
authors.lastname: Yáñez
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodriguez-Franco
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Arce
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Hernández-Guijo
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
mesh_terms: D000814:Aniline Compounds / Q000032:analysis; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects; D016257:Fura-2 / Q000032:analysis; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014966:Xanthenes / Q000032:analysis
chemical_list: D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D002395:Catecholamines; C409648:Fluo 4; D018696:Neuroprotective Agents; D014966:Xanthenes; D018698:Glutamic Acid; D011188:Potassium; D002118:Calcium; D016257:Fura-2