Abstract
Glutamate toxicity causes neuronal death in neurodegenerative diseases; hence, there is a need for therapeutic agents rendering functional neuroprotection. We tested the effects of 17β‐estradiol (estrogen) in rat primary cortical neurons after glutamate exposure. Wright staining and ApopTag assays indicated that 0.5 μM glutamate for 24 hr caused apoptosis. Glutamate‐induced apoptosis correlated with upregulation of calpain, a proapoptotic shift in the Bax:Bcl‐2 ratio, and increased activation of caspase‐3. Pretreatment with 10 nM estrogen prevented apoptosis, attenuated calpain upregulation, shifted the Bax:Bcl‐2 ratio toward survival, and decreased caspase‐3 activation. Single‐cell voltage‐clamp techniques were used to record whole‐cell currents associated with Na^+^ channels, N‐methyl‐D‐aspartate receptor channels, and kainate receptor channels. No significant differences were recorded in membrane capacitance at −70 mV in neurons treated with estrogen or estrogen plus glutamate, relative to controls. Notably, no changes in capacitance indicated that neurons treated with estrogen and glutamate did not experience apoptosis‐associated cell shrinkage. No membrane potential could be recorded in the neurons treated with glutamate due to apoptosis. All recorded currents were similar in amplitude and activation/inactivation kinetics in control neurons and neurons treated with estrogen plus glutamate. Estrogen thus preserved both neuronal viability and function in this in vitro glutamate toxicity model. © 2004 Wiley‐Liss, Inc.