Altered Na(+)-channel function as an in vitro model of the ischemic penumbra: action of lubeluzole and other neuroprotective drugs.
Veratridine blocks Na(+)-channel inactivation and causes a persistant Na(+)-influx. Exposure of hippocampal slices to 10 microM veratridine led to a failure of synaptic transmission, repetitive spreading depression (SD)-like depolarizations of increasing duration, loss of Ca(+)-homeostasis, a large reduction of membrane potential, spongious edema and metabolic failure. Normalization of the amplitude of the negative DC shift evoked by high K+ ACSF 80 min after veratridine exposure was taken as the primary endpoint for neuroprotection. Compounds whose mechanisms of action includes Na(+)-channel modulation were neuroprotective (IC50-values in microM): tetrodotoxin 0.017, verapamil 1.18, riluzole 1.95, lamotrigine > or = 10, and diphenylhydantoin 16.1. Both NMDA (MK-801 and PH) and non-NMDA (NBQX) excitatory amino acid antagonists were inactive, as were NOS-synthesis inhibitor (nitro-L-arginine and L-NAME) Ca(2+)-channel blockers (cadmium, nimodipine) and a K(+)-channel blocker (TEA). Lubeluzole significantly delayed in time before the slices became epileptic, postponed the first SD-like depolarization, allowed the slices to better recover their membrane potential after a larger number of SD-like DC depolarizations, preserved Ca2+ and energy homeostasis, and prevented the neurotoxic effects of veratridine (IC50-value 0.54 microM). A concentration of lubeluzole, which was 40 x higher than its IC50-value for neuroprotection against veratridine, had no effect on repetitive Na(+)-dependent action potentials induced by depolarizing current in normal ACSF. The ability of lubeluzole to prevent the pathological consequences of excessive Na(+)-influx, without altering normal Na(+)- channel function may be of benefit in stroke.
Ashton
D
D
Department of Neuopsychopharmacology, Jansen Research Foundation, Beerse, Belgium.
Willems
R
R
Wynants
J
J
Van Reempts
J
J
Marrannes
R
R
Clincke
G
G
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D010880:Piperidines; D015222:Sodium Channels; D013844:Thiazoles; D014701:Veratridine; C097722:lubeluzole