Zinc-induced neuronal death in cortical neurons

Although Zn2+ is normally stored and released in the brain, excessive expos ure to extracellular Zn2+ can be neurotoxic. The purpose of the present stu dy was to determine the type of neuronal cell death, necrosis versus apopto sis, induced by Zn2+ exposure. Addition of 10-50 mu M ZnCl2 to the bathing medium of murine neuronal and glial cell cultures induced, over the next 24 hrs., Zn2+-concentration-dependent neuronal death; some glial death also o ccurred with Zn2+ concentrations above 30 mu M The neuronal death induced b y 20 mu M Zn2+ was characterized by coarse chromatin condensation, the form ation of apoptotic bodies, and internucleosomal DNA fragmentation. It was a ttenuated in cortical cell cultures prepared from mice null for the bax gen e, and by the caspase inhibitor, benzyloxycarbonyl-val-Ala-Asp-CH2F (ZVAD, 100 mu M), but not by the NMDA receptor antagonist, D-2-amino-5-phosphonova lerate (D-APV, 200 mu M). In contrast, the neuronal death induced by 50 mu M Zn2+ was characterized by plasma membrane disruption and random DNA fragm entation; this death was attenuated by D-APV, but exhibited little sensitiv ity to ZVAD or deletion of bax. These results suggest that Zn2+ can induce cell death with characteristics of either apoptosis or necrosis, depending on the intensity of the Zn2+ exposure.