Effects of U-83836E on glutamate-induced neurotoxicity in dissociated rat cerebellar granule cells

The effects of the lazaroid compound U-83836E on the glutamate-induced prod uction of reactive oxygen species (ROS) were studied in dissociated rat cer ebellar granule cells by flow cytometry. U-83836E completely inhibited ROS production with an estimated IC50 value of 21.7 +/- 9.1 nM. However, U-8383 6E did not inhibit the glutamate-evoked decrease in mitochondrial membrane potential (MMP). Nevertheless, U-83836E (10 nM to 10 mu M) prevented cell d eath induced by 10 mM of glutamate. At concentrations above 10 mu M, U-8383 6E by itself showed slight cytotoxicity, which was significant at a 100 mu M concentration. U-83836E (25 to 200 mu M) also increased the cytosolic cal cium levels in a concentration-dependent manner. Our results indicate that the cytotoxic effects found at micromolar concentrations of U-83836E could be explained by an increase in [Ca2+](i). Finally, since U-83836E did not p revent the MMP decrease evoked by glutamate, it is suggested that antioxida nt pharmacotherapy would not be sufficient to block the neurotoxic effects of glutamate. (C) 1999 Academic Press.