Kimihiro Kasamo

Epileptic seizure of El mouse initiates at the parietal cortex: depth EEG observation in freely moving condition using buffer amplifier

The initiation site of seizure discharges and the relationship between behavioral manifestations and electroencephalography were investigated in the El mouse, a hereditary epilepsy model. The chronic depth electrodes were implanted stereotaxically into the frontal cortex, parietal cortex, temporal cortex, hippocampus, striatum, amygdaloid complex, non-specific nuclei of thalamus and substantia nigra. Electrical activities were recorded in freely moving condition with use of the buffer amplifier devised in the laboratory and behaviors were monitored simultaneously. Seizure spike discharges started in the parietal cortex and spread out into other brain areas. When the hippocampus was involved, the tonic convulsion occurred behaviorally. The paper describes the first direct evidence of the initiation and propagation of seizure discharges in the brain of El mouse.

Antiepileptic effects of allopurinol on EL mice are associated with changes in SOD isoenzyme activities

We have investigated the potential antiepileptic action of superoxide dismutase (SOD) activities in the brain of the epileptic mutant EL mouse. EL mice which experienced frequent seizures (EL[s]) had abnormally low levels of SOD isoenzyme activity in the hippocampal area. Once epileptogenicity was established in these animals, activity of cyanide-sensitive Cu,Zn-SOD was maintained at significantly lower levels than in control mice. However, cyanide-insensitive Mn-SOD activity was not different from non-epileptic controls. In EL mice which had not experienced seizure provoking stimulations and exhibited no seizures (EL[ns]) there was moderately lower levels of SOD isoenzyme activities compared to controls. In spite of the low level of Cu,Zn-SOD activity in EL[s] mice, the Cu,Zn-SOD protein content was high in the hippocampus of these animals, suggesting that inactive Cu,Zn-SOD might be induced during development. After allopurinol (ALP) was given orally to EL[s] mice, Cu,Zn-SOD activities increased dramatically in the hippocampus and seizure activity was decreased. Even after 48 h, when antiepileptic action of ALP was lost, the SOD activity was maintained at the high level associated with initial ALP administration. EL[s] mice also showed DNA fragmentation in the hippocampal CA1 region and the parietal cortex, detected with in situ terminal transferase-mediated dUTP nick labeling with the aid of alkaliphosphatase or peroxidase. The degree of DNA fragmentation was less severe in EL[ns] mice. We propose that abnormalities in region specific Cu,Zn-SOD isoenzyme activity might produce free radicals, leading to DNA fragmentations and cell loss. This might contribute to hippocampal epileptogenesis in EL mice.

Endogenous 5-HT Tonically Inhibits Spontaneous Firing Activity of Dorsal Hippocampus CA1 Pyramidal Neurons Through Stimulation of 5-HT1A Receptors in Quiet Awake Rats: In Vivo Electrophysiological Evidence

The present study was performed to examine an overall effect of endogenous serotonin (5-HT) on the spontaneous firing activity of the dorsal hippocampus CA1 pyramidal neurons in quiet awake rats. A selective 5-HT1A antagonist N-[2–[4–(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635: 0.03–0.2 mg/kg, s.c.) significantly increased the firing activity. A depletion of 5-HT with parachlorophenylalanine (PCPA: 500 mg/kg/day × 3 days) completely abolished this increasing effect of WAY-100635. The baseline spike frequency of the PCPA-treated rats (3.90 ± 0.39 Hz) was significantly higher than that of the vehicle-treated rats (2.09 ± 0.19 Hz). A 5-HT2A antagonist ritanserin (1 mg/kg, i.p.) and a 5-HT3/4 antagonist 2-methoxy-4-amino-5-chloro benzoic acid 2-(diethylamino) ethyl ester (SDZ-205557: 3 mg/kg, s.c.) did not modify the firing activity and the increasing effect of WAY-100635. These results suggest that, in quiet awake rats, endogenous 5-HT would tonically inhibit the spontaneous firing activity of the CA1 pyramidal neurons mainly through stimulating 5-HT1A receptors.

Chronological changes of MRI findings on striatal damage after acute cyanide intoxication: Pathogenesis of the damage and its selectivity, and prevention for neurological sequelae: A case report

SummaryA 31-year-old male technician in an electroplating factory, who had been suffering from the temporal lobe epilepsy for 24 years and from hypertension for 3 years, took an unknown amount of potassium cyanide apparently over the lethal dose, in an attempt to commit suicide. He was treated successfully and survived without any neurological sequelae. The electroencephalograms and the nature of the seizures were not different before and after the poisoning. The T2-weighted magnetic resonance images at 9 and 51 days after the poisoning showed bilateral elevation of signals in the caudate nuclei and the putamina. At the 143th and 286th days, T2-weighted high-resonance areas were restricted to the lateral portion of the putamina. The T1-weighted images at the 51st day showed abnormal signal elevations in both putamina, while those of 9th, 143th and 286th days were mainly normal. Selective vulnerability of the putamen and the caudate nucleus may be due to their specific structural properties of high oxygen and glucose utilization, and enzyme distribution. Both chronological changes of striatal damage and the absence of neurological sequelae in this patient suggest the possibility that anti-epileptics and a calcium antagonist played a neuroprotective role in the acute cyanide intoxication.

Effects of Zopiclone, Triazolam, and Nitrazepam on Standing Steadiness

We examined the effects of the nonbenzodiazepine hypnotic zopiclone and the benzodiazepine hypnotics triazolam and nitrazepam on standing steadiness. Eight healthy volunteers received placebo, zopiclone (7.5 mg), triazolam (0.25 mg), and nitrazepam (5 mg) in a random-order, double-blind crossover design. Postural sway was assessed before and 1 and 2 h after drug administration using a stabilometer connected to a microcomputer. Triazolam significantly impaired standing steadiness. Zopiclone also impaired standing steadiness but the degree of impairment seemed to be less marked. Nitrazepam 5 mg had no significant effects on postural sway. Triazolam 0.25 mg, zopiclone 7.5 mg, and nitrazepam 5 mg, which are reported to be equipotent to each other as hypnotics, are not equipotent with respect to their effects on postural sway.

Effects of several 5-HT1A agonists on hippocampal rhythmical slow activity in unanesthetized rats

We examined the effect of 5-hydroxytryptamine (5-HT)1A agonists on walking related, atropine-resistant, rhythmical slow activity (wr-RSA) of the hippocampus in rats. Selective 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), flesinoxan, buspirone and ipsapirone significantly decreased the power value of 7-9 Hz band activity and the median frequency of wr-RSA. The order of potency was 8-OH-DPAT > flesinoxan = buspirone in power reduction. The 5-HT1A antagonists, (-)pindolol, (-)propranolol and spiperone, inhibited the effect of 8-OH-DPAT on wr-RSA. Pretreatment with parachlorophenylalanine did not abolish the effect of 8-OH-DPAT. These results indicate that 5-HT1A agonists reduce both power and median frequency values of wr-RSA through activation of post-synaptic 5-HT1A receptors in the forebrain in unanesthetized rats, in vivo.

Effects of a benzodioxan derivative MKC-242 on the firing activity of the dorsal hippocampus CA1 pyramidal neurons in awake and urethane- anaesthetized rats: in vivo electrophysiological evidence for a 5-HT 1A agonistic property.

The aim of the present in vivo study was to determine whether a benzodioxan derivative MKC-242, (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole hydrochloride, possesses an agonistic activity at postsynaptic serotonin (5-HT)1A receptors in the rat hippocampus when administered systemically. We examined the effects of acute administrations of MKC-242 on the firing activities of dorsal hippocampus CA1 pyramidal neurons. In quiet awake rats, s.c. administrations of MKC-242 significantly decreased the spontaneous firing activity in a dose-dependent manner at doses of 0.3-6 mg/kg. In urethane-anaesthetized rats, i.v. injections of MKC-242, at cumulative doses of 0.3-3 mg/kg, also significantly and dose-dependently inhibited the firing activity induced by microiontophoretically applied quisqualate. These decreasing effects were antagonized by the selective 5-HT1A antagonists WAY-100135 (5 mg/kg, s.c.) and WAY-100635 (0.2 mg/kg, s.c. to the awake rats and 0.4 mg/kg, i.v. to the anaesthetized rats), thereby confirming that MKC- 242 decreased the firing activities by stimulating 5-HT1A receptors. The selective depletion of 5-HT produced by the 3-d administration of the 5-HT synthesis inhibitor, parachlorophenylalanine (500 mg/kg.d, i.p.), did not affect the decreasing effect of MKC-242 in the awake animals, indicating that postsynaptic 5-HT1A receptors mediated the decreasing effect. The present results provided the first in vivo electrophysiological evidence that MKC-242, when systemically administered, exerts a 5-HT1A agonistic action at the postsynaptic level.

Antiepileptic effects of allopurinol involved in hippocampal specific SOD (superoxide dismutase) induction in the mutant El mouse.

Recently the xanthine oxidase inhibitor, allopurinol, has been clinically demonstrated to exert antiepileptic effects: particularly on secondarily generalized seizures.’ The El mouse is an epileptic mutant model of secondarily generalized seizure.6 Several lines of evidence indicate that in the El, the parietal cortex plays an important role in seizure initiation and the hippocampus plays a role in the generalization of se iz~res .~ And the developmental formation of the “Focus Complex” which is mainly constituted from the parietal cortex and hippocampus should be deeply involved in the epileptogene~is.~ Antiepileptic effects of allopurinol were determined in the El. Furthermore, the mode of action of allopurinol was investigated by measuring the activities of superoxide dismutase (SOD) according to the time course after the administration of allopurinol.