Neuropharmacological Approach to Epilepsy: A New Point of View.

(1)Development of Neuropharmaclogical Studies on Current Epileptic Situations Drugs for treatment of epilepsy include those that (I) inhibit Na+ channels (such as phenytoin), (2) suppress voltagcdependcnt Ca + channels (such as ethosuximide), and (3) interact with tlic GABA system (such as valproate). However, 20%‐30% of patients with cpilepsy are estimated to be refractory to current anticpileptic drugs available at present, suggesting that epilepsy is a complicated discase not due to a single pathogenesis hut rathcr a variety ofdiffercnt etiological sources. Epilcpsy studics are developing with use of model iinimals including genctically defined ones and drug‐ or stimulus‐ treatcd animals. The pathogenesis of cpilepsy is considered as follows. (II)Abnormality of excitatory and/or inhibitatory synaptic transmission : (a) Abnormal transmission of glutamatergic systems can be categorizcd as: (i) existence of a giant EPSP, called the paroxysmal depolarization shift in epileptic focal neurons, (ii) excessive release of glutamatc i n thc focal area, (iii) hyperfunction of NMDA receptors (e.g. rcflex epilcpsy such as audiogenic seizures in DBA/2 mice), (iiii) an i n glutamate receptors (e.g. in hippocampal‐kindlcd animals plex partial seizures); (b) Abnormal GABAcrgic lransmission: (i) a decrcase in benzodiazepine binding sitcs due to point mutation of GABA, reccptor subunits (e.g. B2/B2 in genetic absence cpilepsy rat 01’ Strasburg), (ii) hyperscnsitivity to GABA of GABA, receptors, (iii) involveincnt ol thalamo‐cortical circuit in absence seizures, it., hyperfunctions of GABA, receptors and Ca 2+ channels. (2)Abnormality of voltage‐dependent Ca 2+ channels : (i) abnorinal Ca 2+ channcl hyperfunction in hippocampal CA3 ncurons (e.g. spon‐ tancously epilcptic rat [SER] and Noda epileptic rat [NERI), (ii) point mutation 0 1 a l A subunit of P type Ca2+ channel (e.g. tottering mouse), (iii) long‐lasting enhancemcnt of Ca2+ channel current in hippocampal CAI ncurons (e.g. kindled animal). (3)Abnormality or neuron network : (i) failure or catecholaminergic control on appearance of synchronized bursts, (ii) failure of inferior colliculus control i n audiogenic seizures and inhibitory action of pars reticulata of substantia nigra. Further progress in studies on the pathogenesis of cpilepsy will lead to discovcry of novcl therapeutic drugs and treatments against refractory epilepsy. (2) News on neuroscience session Regarding thc role of the glutamatergic systcm, two reports were doctimcnted. First, glutamate transporter located on the astroglia cells (GLAST) was, contrary to expectation, demonstratcd not to play an important role in regulation of kindling‐induced seizurcs using GLAST knock‐out micc. However, GLAST appeared to control generalization of kindling or pentylentetrazolc‐induced scizurcs (NS‐2). The second paper showcd that mnisaiiiide inhibited K+nduced glutamate rclease, stiggcsting on voltagc‐depcndent Ca 2+ channels (probably P type Ca 2+ channels) (NSI). Regarding GABA, receptors, intcrestingly, kninatc‐induced sciz.urcs resulted in alterations of mRNA of GABA, reccptor subunits (NS‐4). Finally, i n studies using cpileptic focal tissue obtaincd irom temporal epilepsy patients and kindled animals, an increase in apoptosis‐related genes such as hcl‐2 and hax was suggested to relate with appcarancc o1 seizures and/or scizure waves. (NS‐3).Thcse impressive findings will Further facilitate ncuropharmacological studies on the pathogencsis of epilcptic seizurcs and therapy.