Calcium ionophores can induce either apoptosis or necrosis in cultured cortical neurons

Cultured cortical neurons exposed for 24 h to low concentrations of the Ca2 + ionophores, ionomycin (250 nM) or A-23187 (100 nM), underwent apoptosis, accompanied by early degeneration of neurites, cell body shrinkage, chromat in condensation and internucleosomal DNA fragmentation. This death could be blocked by protein synthesis inhibitors, as well as by the growth factors brain-derived neurotrophic factor or insulin-like growth factor I. If the i onomycin concentration was increased to 1-3 mu M, then neurons underwent ne crosis, accompanied by early cell body swelling without DNA laddering, or s ensitivity to cycloheximide or growth factors. Calcium imaging with Fura-2 suggested a possible basis for the differential effects of low and high con centrations of ionomycin. At low concentrations, ionomycin induced greater increases in intracellular Ca2+ concentration in neurites than in neuronal cell bodies, whereas at high concentrations, ionomycin produced large incre ases in intracellular Ca2+ concentration in both neurites and cell bodies. We hypothesize that the ability of low concentrations of Ca2+ ionophores to raise intracellular Ca2+ concentration preferentially in neurites caused e arly neurite degeneration, leading to loss of growth factor availability to the cell body and consequent apoptosis, whereas high concentrations of ion ophores produced global cellular Ca2+ overload and consequent necrosis. (C) 1999 IBRO. Published by Elsevier Science Ltd.