Tsugutaka Ito

Effects of zonisamide (AD-810) on tungstic acid gel-induced thalamic generalized seizures and conjugated estrogen-induced cortical spike-wave discharges in cats.

Summary: Effects of zonisamide (AD‐810, CI‐912) were examined on tungstic acid gel‐induced thalamic generalized seizures and conjugated estrogen‐induced cortical spike‐wave discharges in gallamine‐immobilized cats. Zonisamide prolonged the interictal periods of the generalized seizures by thalamic (centralis lateralis) application of tungstic acid gel (50 μl) and, at the higher doses, abolished the seizures; its potency was near that of phenobarbital. Zonisamide abolished the spike‐wave discharges by cortical (posterior lateralis) application of 2% conjugated estrogens (CE); its potency was stronger than that of dipropylacetate or trimethadione, but slightly less than that of phenytoin, phenobarbital, or carbamazepine. Zonisamide did not affect the posttetanic potentiation of the monosynaptic reflexes (ventral root potentials) in urethane‐chloralose–anesthetized spinal rats. From these results, it is suggested that zonisamide suppresses both seizures originating from the thalamus and the cortex through the mechanism differing from that of phenytoin. Zonisamide appears to be effective in primary generalized seizures, especially the grand mai epilepsies, in addition to being effective in cortical epilepsies.

Physostigmine induces in rats a phenomenon resembling long-term potentiation

The study dealt with a phenomenon similar to long-term potentiation of hippocampal population spikes that was observed with a high dose of physostigmine given to rats. The population spikes in the dentate granule cells in anesthetized rats were enhanced to 135, 152 and 167% of the control level 60, 120 and 240 min after the administration of physostigmine (0.1 mg/kg i.v.), respectively. The time course of the enhancement was consistent with that of blocked paired pulse inhibition by physostigmine in anesthetized rats. Such a block of paired pulse inhibition was seen at the observation of the long-term potentiation phenomenon to tetanic stimulation (100 Hz, 2 s). Perfusion of physostigmine (10(-5) M) or bicuculline (10(-6) M) elicited second spikes following the population spikes in CA1 pyramidal cells. The second spikes elicited by physostigmine were decreased by scopolamine (10(-6) M) and muscimol (5 x 10(-7) M), while those caused by bicuculline were decreased by muscimol but not by scopolamine. It is suggested that physostigmine induces a long-term potentiation-like phenomenon through a transient, abrupt increase in excitability and the subsequent block of recurrent GABAergic inhibition in the hippocampus.

Effect of Anticonvulsants on Cortical Focal Seizure in Cats

Electrical stimulation of the visual cortex evoked the cortical focal seizure restricted in the neighbor cortex of the stimulated area in gallamine‐immobilized cats. The present experiment was performed to clarify the participation of anticonvulsants in the cortex itself. Phenytoin and carbamazepine depressed the focal seizure, as indicated by the shortening of seizure duration and the suppression of spreading. In addition, the high‐frequency components in seizure disappeared with the use of these drugs. Phenobarbital and diazepam also shortened the seizure duration. However, the high‐frequency components did not disappear although seizure amplitude was depressed. Trimethadione, acetazolamide, and dipropylacetate facilitated the focal seizure. From these results, the participation of the drugs affecting grand mal and partial epilepsies in the cortex is suggested. In addition, this experimental model is thought to be useful in elucidating possible modes or mechanisms of anticonvulsant action on cortical neurons by analyzing, after drug administration, the changes in seizure patterns which seem to reflect underlying neuronal changes.

5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370

The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-)-N-[1-methyl-4-(3-methyl-benzyl)hexahydro-1H-1,4-diazepin-6- yl]-1H- indazole-3-carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthetized rats, DAT-582 antagonized 2-methyl-5-HT-induced bradycardia with an ED50 value of 0.25 microgram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i.v.)-induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.

Effect of anticonvulsants on spiking activity induced by cortical freezing in cats.

Summary: In an attempt to know whether the existing anticonvulsants act on epileptogenic focus, the effect on SA induced by freezing of the visual cortex was examined in gallamine‐iimmobilized cats. The SA was localized in the neighbor or ipsilateral cortex of the freezing area; little epileptiform activity was produced in the contralateral anterior cortex, and ipsilateral thalamus and hippocampus. Spike frequency and its amplitude were stable over 8 hr. Diazepam suppressed SA and decreased spike frequency and its amplitude. Dipropylace‐tate and acetazolamide also suppressed SA. On the other hand, phenobarbital, carbamazepine, and a high dose of phenytoin enhanced SA and increased the spike frequency. Low doses of phenytoin and trimethadione were without effect in this aspect. Taurine suppressed SA and changed the spikes to wave‐like forms. The EEG arousal response was depressed with phenobarbital, carbamazepine, diazepam, and a high dose of phenytoin, but not with the other drugs examined. From these results, it is suggested that diazepam, dipropylace‐tate, acetazolamide, and taurine depress the epileptogenic focus activity itself without relation to the activating system.