Akira Takazawa

Effects of carbamazepine and valproic acid on brain immunoreactive somatostatin and γ-aminobutyric acid in amygdaloid-kindled rats

Somatostatin and gamma-aminobutyric acid (GABA) concentrations were evaluated in the brain of kindled rats treated chronically with carbamazepine and valproic acid. Kindled seizures were almost completely blocked by treatment with carbamazepine, whereas the effect of valproic acid was partial, suppressing only generalized seizures. The duration of after-discharge in amygdala was suppressed by carbamazepine not by valproic acid. Carbamazepine induced a decrease in immunoreactive somatostatin concentration and an increase in GABA concentration in the temporal cortex of kindled rats. Valproic acid induced only an increase in GABA concentration. The results suggest that somatostatin may be associated with the suppression of focal seizure in amygdala and GABA may have a role in the suppression of generalized seizures.

Potent and long-lasting anticonvulsant effects of 1-naphthylacetyl spermine, an analogue of Joro spider toxin, against amygdaloid kindled seizures in rats.

The anticonvulsant effect of 1-naphthylacetyl spermine (1-NA-Spm), an analogue of Joro spider toxin, against amygdaloid kindled seizures was studied in rats. 1-NA-Spm (10, 20 and 40 micrograms/rat) dose-dependently improved kindled seizures and shortened the afterdischarge duration 30 min after the administration. The anticonvulsant effect was observed even one day after the drug, and then gradually disappeared within 4 days. The present findings demonstrate that 1-NA-Spm acts as a potent and long-acting anticonvulsant against amygdaloid kindled seizures, and also suggest, together with the previous findings, that the calcium-permeable AMPA receptors, which are selectively antagonized by 1-NA-Spm, play a critical role in the seizure generation mechanism of amygdaloid kindling.

Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Summary:  Purpose: Nefiracetam (NEF) is a novel pyrrolidone‐type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition‐enhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy.

Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats

Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Nefiracetam (25, 50 and 100 mg/kg po) had no effect on the behavioral seizures and dose-dependently inhibited the hippocampal damage. In contrast, levetiracetam, a pyrrolidone-type antiepileptic drug, inhibited neither. Valproic acid and ethosuximide prevented the hippocampal damage without attenuating the behavioral seizures as nefiracetam. Zonisamide and phenytoin did not inhibit the behavioral seizures, while zonisamide enhanced the hippocampal damage and phenytoin increased the lethality rate. Carbamazepine inhibited the behavioral seizures at 50 mg/kg and enhanced that at 100 mg/kg, and it completely inhibited the hippocampal damage at both doses. We have previously reported that anticonvulsant spectrum of nefiracetam paralleled that of zonisamide, phenytoin or carbamazepine in standard screening models. However, the pharmacological profile of nefiracetam was closer to valproic acid or ethosuximide than that of zonisamide, phenytoin or carbamazepine in this study. These results suggest that anticonvulsant spectrum and mechanism of nefiracetam are distinct from those of standard antiepileptic drugs, and nefiracetam possesses a neuroprotective effect that is unrelated to seizure inhibition.

Effects of Nefiracetam, a Novel Pyrrolidone‐type Nootropic Agent, on the Amygdala‐kindled Seizures in Rats

Summary:  Purpose: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition‐enhancing effects. The present study focused on the effects of NEF in amygdala‐kindled seizures and its potential for antiepileptic therapy.

Pharmacological Characterization of EEG Spikes and Seizures Induced by a Specific Calcium‐Permeable AMPA Receptor Antagonist, 1‐Naphthylacetyl Spermine (1‐NA‐Spm)

Purpose,: It is known that AMPA receptor has a crucial role in seimre generation and epileptogcnesis. Joro spider toxin (JSTX) sclectively blocks the calciurn‐permeable AMPA receptor a s a channel blocker. We have reported that a synthetic JSTX analoguc, 1 ‐NA‐Spin, suppresses amygdaloid and hippocampal kindled seizures in a dosedependent manner. This analogue induces EEG spikes both on the kindled animals and on the niiivc animals. The spike‐inducing effect of I ‐NA‐Spm is not directly related to the anticonvulsant effects of this drug, because time‐course of the inhibitory effects on the kindled seiurcs is different from that of the spike‐inducing effect. The drug soinctiines produces myoclonus and generalized seizures coinciding with the spike induction. To elucidate the mechanism underlying these proconvulsant cffects, participants of the AMPA, NMDA, and GABA transmitter systems to the I ‐NA‐Spin induced effects were tested.

Cysteamine potentiates entorhinal activation of dentate gyrus granule cells in rats

A dense plexus of somatostatin-positive fibers and varicosities is observed in the outer two-thirds of the dentate gyrus molecular layer where the glutamatergic perforant path afferents from the entorhinal cortex terminate. To test for a functional interaction between these two pathways, we examined the effects of cysteamine, which enhances somatostatin release for a few hours after administration but produces subsequent depletion of somatostatin lasting several days, on perforant path evoked potentials recorded in the dentate gyrus. Cysteamine (50-400 mg/kg, IP) increased the population spike dose-dependently both in anesthetized and in awake rats, but the slope of the population excitatory postsynaptic potential (EPSP) was left unchanged or even decreased. The antidromic population spike evoked by mossy fiber stimulation was not changed by cysteamine. The change is thought to be due to the increase in slope of the EPSP-spike relationship. In the hippocampal slice preparation, a similar effect of the drug (1-5 mM) on dentate evoked potentials was observed, suggesting that cysteamine acts through its effects on somatostatin in the hippocampus itself. In chronically implanted awake animals, the perforant path population spike was increased 1 h after cysteamine but returned to the predrug level by 24 h when somatostatin seemed to be depleted. These results suggest that hippocampal somatostatin released by cysteamine potentiates the response of dentate granule cells to perforant path input, without directly affecting synaptic transmission or general cell excitability.

Laminar Analysis of the Hippocampal-Evoked Potential in the El Mouse

Since the discovery in 19544 of an El mouse, an inbred mutant strain and excellent model for idiopathic epilepsy, remarkable electrophysiological and biochemical contributions had been a~hieved .~ alo However, no morphological finding was reported except our preliminary By the 2DG autoradiographylO and depth EEG (our unpublished data) , the hippocampus (hip) was found to play important roles in the seizure mechanism of the El mouse. Here we report slight but significant histopathological and neurophysiological alterations in the El hip and dentate fascia (df), suggesting a close functional anatomical correlation and a possible synaptic plasticity.

Biphasic modulation of spontaneous activities of entopeduncular neurons by systemic application of apomorphine in anesthetized cats

The responses of entopeduncular neurons to apomorphine were investigated with extracellular recording methods in anesthetized cats. Apomorphine was applied intravenously in increasing doses, which cumulatively doubled with each addition (5-640 micrograms/kg). The spontaneous firing rates of entopeduncular neurons, which were inhibited by electrical stimulation of the caudate nucleus, increased when lower doses of apomorphine (5-20 micrograms/kg) were applied. However, higher doses (40-640 micrograms/kg) produced a dose-dependent decrease in the firing rate. The results suggest that there are direct and indirect effects of systemically administered apomorphine on entopeduncular neurons which may contribute to biphasic responses in the spontaneous discharge rate.