PRIMING OF CULTURED NEURONS WITH SABELUZOLE RESULTS IN LONG-LASTING INHIBITION OF NEUROTOXIN-INDUCED TAU-EXPRESSION AND CELL-DEATH

Sabeluzole was described to have antiischemic, antiepileptic, and cogn itive-enhancing properties, and is currently under development for Alz heimer's disease. Recently, it was reported that repeated treatments w ith sabeluzole protect cultured rat hippocampal neurons against NMDA- and glutamate-induced neurotoxicity. We evaluated the possibility that sabeluzole elicits neuroprotection by acting, either directly or indi rectly, on tau proteins. We found that repeated treatments during deve lopment of primary cultures of cerebellar granule cells with nanomolar concentrations of sabeluzole resulted in mature cells that were resis tant to the excitotoxicity induced by glutamate. Also, sabeluzole trea tment specifically prevented the glutamate-induced increase of tau exp ression without modifying the basal pattern of expression of tau prote ins, as shown by measurement of mRNA and protein levels. In human neur oblastoma cell line SH-SY5Y, differentiated by treatment with retinoic acid, doxorubicin increased tau immunoreactivity, and later induced c ell death. Both effects were prevented by sabeluzole. Our data indicat e that increased tau expression is a common response to different type s of cells to neurotoxic agents, and that sabeluzole-induced neuroprot ection is functionally associated with the prevention of the injury-me diated increase of tau expression. (C) 1997 Wiley-Liss, Inc.