Vol. 286, Issue 1, 201-214, July 1998

Influence of Lubeluzole on Voltage-Sensitive Ca⁺⁺ Channels in Isolated Rat Neurons

R. Marrannes, E. De Prins and G. Clincke

Department of Neuropsychopharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium

Lubeluzole is neuroprotective in a photochemical stroke model, whereas the (R)-enantiomer of the same molecule is not [De Ryck M, Keersmaekers R, Duytschaever H, Claes C, Clincke G, Janssen M and Van Reet G (1996) J Pharmacol Exp Ther 279:748-758]. We investigated the effects of lubeluzole and the (R)-enantiomer on voltage-sensitive Ca⁺⁺ channels of isolated rat dorsal root ganglion cells, using whole-cell voltage-clamp, with Ba⁺⁺ as the charge carrier. Both compounds blocked the low-voltage-activated Ba⁺⁺ current (iLVA or T current) with an IC₅₀ value of 1.2 µM. Lubeluzole and the (R)-enantiomer also blocked the high-voltage-activated calcium channel current (iHVA), with IC₅₀ values of 2.6 and 3.5 µM, respectively, and accelerated the apparent inactivation of iHVA. This acceleration was more pronounced with lubeluzole than with the (R)-enantiomer at 3 and 10 µM. Both compounds produced a clear tonic block of iLVA and iHVA, even in the absence of previous stimulation. Lubeluzole and the (R)-enantiomer induced a negative shift of the inactivation curve of iLVA and slowed down the recovery from inactivation. This resulted in a stronger inhibition of iLVA at more depolarized 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 ganglion 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 inhibition of Ca⁺⁺ channel currents does not explain the stereospecificity of the neuroprotective properties of lubeluzole in vitro and in vivo.