Shigeo Watabe

Differential inhibition of transient and long-lasting calcium channel currents by benzodiazepines in neuroblastoma cells

The effects of diazepam, nitrazepam, clonazepam, and Ro5-4864 on transient (type I) and long-lasting (type II) calcium channels associated with low-affinity benzodiazepine receptors were investigated using the whole-cell patch-clamp technique. Clonazepam (100 microM), a specific agonist for the central-type benzodiazepine receptor, reduced transient currents through the type I calcium channel by 40% without affecting long-lasting currents through the type II calcium channel. Diazepam and nitrazepam (100 microM), non-specific agonists for both the central- and peripheral-type benzodiazepine receptors, reduced both transient and long-lasting currents equally by 25-30%. A similar non-selective inhibition was observed by Ro5-4864 (1-10 microM), a specific agonist for the peripheral-type benzodiazepine receptor. It is concluded that the two calcium channel types are regulated differentially by two different kinds of benzodiazepines; central-type for type I channel and peripheral-type for both type I and type II channels.

Nootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL mice

Abstract: Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5‐4864, a specific agonist for peripheral‐type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5‐4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5‐4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5‐4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam ≫ oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.

The Effects of Pyrethroid Insecticides on Synaptic Transmission in Slices of Guinea Pig Olfactory Cortex

The synthetic pyrethroids are potent and widely used insecticides. Pyrethroids modify the ionic permeability of nerve membranes and produce distinctive poisoning syndromes in insects and mammals (1,4,5). These agents have been divided into two major classes on the basis of their structures, neurophysiological and toxicological actions (2). Pyrethroids containing an α-cyano substituent have been classified as type II pyrethroids and include the agents deltamethrin and fenvalerate. Type II pyrethroid insecticidal action is associated with long nerve discharges and nerve membrane depolarization and these compounds produce a poisoning syndrome in mammals characterized by tremors, choreoathetosis and tonic Scizures. The noncyano pyrethroids (type I) include the agents permethrin and tetramethrin and produce extensive repetitive firing in isolated invetebrate nerve preparations. The type I poisoning syndrome in mammals is characterized by hyperactivity and tremor.

2903 Antiepileptic effects of nootropic agent, nefiracetam. — In vivo study of epileptic mutant. El Mice

Dystonia tends to generalize involving mainly in the trunk and proximal portion of the extremities in pediatric patients, while it often localizes in the face, neck and hand in adult patients. Previously, we described focal dystonia in adult patients was well controlled by VL thalamotomy. For treatment of dystonia with onset under 10 years of age (n=9), we carried out stereotactic VL thalamotomy in 8 patients and posteroventral pallidotomy (PVP) in 5. Thalamotomy lightened dystonia principally in the face, neck and hands, however, it failed to improve the main motor signs in the trunk and legs. PVP dramatically abolished the central dystonia in the most patients who had only a little benefit from tbalamotomy previously undergone. The surgical effects lasted for years without medical treatments. PVP is well known to alleviate gait and postural problems in Parkinson’s disease possibly by modifying function of the descending pallido-reticula-spinal pathway. Present findings suggest that pathogenesis of dystonia concerns with dysfunction of two pallidal pathway which organize different somatotopy and develop with time lag.