Exacerbation of NMDAInduced Neuronal Death by PREGS

We have examined a number of steroids for their ability to modulate NMDA-induced neuronal death. Consistent with its ability to potentiate NMDA induced currents and increases in intracellular Ca2+, PREGS exacerbates the toxic effects of NMDA exposure

Fig. 4. Steroid modulation of NMDA-induced whole cell currents and NMDA-induced increases in intracellular calcium are correlated. Calcium influx experiments were carried out on cultures of rat hippocampal neurons. Whole cell currents were measured in chick spinal cord neurons at a holding potential of -70 mV. Values are means ± SEM of the percentage change, calculated as (response in presence of steroid/control response) - 1 x 100%. When the percentage change in NMDA-induced whole cell current are plotted against the percentage change in NMDA-induced calcium increase a strong positive correlation is observed (r = 0.973), suggesting that steroids are direct modulators of the NMDA receptor. 3a5pS and 3a5pS refer to pregnanolone sulfate and epiallopregnanolone sulfate, respectively, whereas 3a5pHS is pregnanolone hemisuccinate. E and E17HS are estradiol and 17p-estradiol 17-hemisuccinate, respectively.

Fig. 4. Steroid modulation of NMDA-induced whole cell currents and NMDA-induced increases in intracellular calcium are correlated. Calcium influx experiments were carried out on cultures of rat hippocampal neurons. Whole cell currents were measured in chick spinal cord neurons at a holding potential of -70 mV. Values are means ± SEM of the percentage change, calculated as (response in presence of steroid/control response) - 1 x 100%. When the percentage change in NMDA-induced whole cell current are plotted against the percentage change in NMDA-induced calcium increase a strong positive correlation is observed (r = 0.973), suggesting that steroids are direct modulators of the NMDA receptor. 3a5pS and 3a5pS refer to pregnanolone sulfate and epiallopregnanolone sulfate, respectively, whereas 3a5pHS is pregnanolone hemisuccinate. E and E17HS are estradiol and 17p-estradiol 17-hemisuccinate, respectively.

on rat hippocampal neurons when present during acute NMDA exposure, but does not increase neuronal death in the absence of NMDA or when added after NMDA washout (110), suggesting that the exacerbation of neuronal death caused by PREGS requires the simultaneous activation of NMDA receptors. In addition, potentiation of chronic NMDA-induced neuronal death by PREGS is completely blocked by MK-801. Taken together, these results support a selective pharmacological interaction of pregnenolone sulfate with NMDA receptors.

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