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, 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 microM. Lubeluzole and the (R)-enantiomer also blocked the high-voltage-activated calcium channel current (iHVA), with IC50 values of 2.6 and 3.5 microM, respectively, and accelerated the apparent inactivation of iHVA. This acceleration was more pronounced with lubeluzole than with the (R)-enantiomer at 3 and 10 microM. 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 showed 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.
Marrannes
R
R
Department of Neuropsychopharmacology, Janssen Research Foundation, Beerse, Belgium.
De Prins
E
E
Clincke
G
G
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013844:Thiazoles / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; C097722:lubeluzole