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 mu M. At 10 mu M, 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 mu M). At 10 mu M, ITH/IQM also inhibited the Ca2+-dependent outward K+ current, leaving untouched the voltage-dependent component of I-K. 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. (C) 2011 Elsevier B.V. All rights reserved.