INFLUENCE OF LUBELUZOLE ON VOLTAGE-SENSITIVE CA++ CHANNELS IN ISOLATED RAT NEURONS

Lubeluzole is neuroprotective in a photochemical stroke model, whereas the (R)-enantiomer of the same molecule is not [De Ryck M, Keersmaeke rs R, Duytschaever H, Claes C, Clincke G, Janssen M and Van Reet G (19 96) J Pharmacol Exp Ther 279:748-758]. We investigated the effects of lubeluzole and the (R)-enantiomer on voltage-sensitive Ca++ channels o f isolated rat dorsal root ganglion cells, using whole-cell voltage-cl amp, with Ba++ as the charge carrier. Both compounds blocked the low-v oltage-activated Ba++ current (iLVA or T current) with an IC,, value o f 1.2 mu M. Lubeluzole and the (R)-enantiomer also blocked the high-vo ltage-activated calcium channel current (iHVA), with IC50 values of 2. 6 and 3.5 mu M, respectively, and accelerated the apparent inactivatio n of iHVA. This acceleration was more pronounced with lubeluzole than with the (R)-enantiomer at 3 and 10 mu M. Both compounds produced a cl ear tonic block of iLVA and iHVA, even in the absence of previous stim ulation. Lubeluzole and the (R)-enantiomer induced a negative shift of the inactivation curve of iLVA and slowed down the recovery from inac tivation. This resulted in a stronger inhibition of iLVA at more depol arized conditioning potentials and higher stimulation frequencies. The block of iHVA was voltage and frequency dependent. Lubeluzole and the (R)-enantiomer also blocked iHVA in isolated rat superior cervical ga nglion cells and cerebellar Purkinje cells. The Ca++ channel-blocking properties of lubeluzole may contribute to its neuroprotective effect. However, the small difference between the two enantiomers in inhibiti on of Ca++ channel currents does not explain the stereospecificity of the neuroprotective properties of lubeluzole in vitro and in vivo.