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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.