Atsushi Noda

NER rat strain: a new type of genetic model in epilepsy research.

Summary: Purpose: We characterized and evaluated as an animal model of epilepsy NER, a new epileptic rat strain, which was developed by inbreeding rats with spontaneous tonic‐clonic seizures in a stock of Crj:Wistar.

Chromosomal mapping of genes for epilepsy in NER : a rat strain with tonic-clonic seizures

Summary: Purpose: NER is a mutant rat strain that exhibits spontaneous tonic‐clonic convulsions accompanied by epileptic discharges on ictal EEG and serves as a model for generalized tonic‐clonic seizures in humans. Our previous experiments have suggested that a major autosomal recessive gene and several minor genes regulate the inheritance of tonic‐clonic seizures in NER. The purpose of this study was to confirm the mode of inheritance and to locate the causative genes for epilepsy in NER on the rat genetic map.

Induction of convulsive seizures by acoustic priming in a new genetically defined model of epilepsy (Noda epileptic rat: NER)

Noda epileptic rat (NER) is a mutant rat, found in a Crj: Wistar colony, which exhibits a tonic clonic convulsion spontaneously about once per 30 h from 14 weeks of age. We performed modified acoustic priming, that is, repeated weekly sound stimulations from 3 weeks of age. In addition, characteristics of audiogenic seizure (AGS), and ictal/interictal electroencephalograms (EEGs) were examined. We also studied the effect of repeated weekly stimulations from 14 weeks of age on AGS susceptibility in another NER. From 9 weeks of age, the NER primed from 3 weeks of age had a high incidence (100%) of AGS: a typical seizure was composed of sudden wild running and/or jumping (WRJ) followed by clonic or tonic-clonic convulsion. The severity and the duration of the AGS were intensified and prolonged with an increase in age, respectively. By contrast, the NER repeatedly stimulated from the age of 14 weeks, rarely showed AGS (20-40(%). The majority of the seizures in this NER were WRJ. The cortical and hippocampal EEG during the tonic convulsion showed a low-voltage spike-wave (5-7 Hz). This evolved into a high-amplitude spike- or polyspike-waves associated with the clonic convulsion. Immediately after cessation of the seizures, the EEG showed a flattening or diffuse slowing. In interictal EEG analysis, sporadic spikes predominantly in the hippocampus and spike-wave bursts in both the cortex and hippocampus occurred from 11 and 20 weeks of age, respectively. These results indicate that AGS susceptibility in NER can be induced consistently by modified acoustic priming and this rat strain is a new genetic model useful for experimental studies of human epilepsy.

Induction of Seizures and Ictal Electroencephalogram in a New Genetically Defined Rat, Noda Epileptic Rats.

such as facial twitching and mastication, were less frequently observed. Pathologic examination revealed that, in the control group, the PRC was not affected. In rats with PRC lesions, slight vacuolation and a surrounding degenerative lesion with slight gliosis were found. McIntyre et al. (1993) demonstrated that PRC kindling developed faster and that the latency from the onset of the stimulus to initiation of forelimb clonus was shorter compared with amygdaloid kindling. These results prompted us to study the role of the PRC in KA-induced seizures. In our study, a lesion of the PRC appeared to suppress propagation of seizure discharges from the limbic system to the sensorimotor cortex and to reduce motor manifestations, such as facial twiching, mastication, and forelimb clonus. These results suggest that the PRC plays an important role in the seizure discharges secondarily generalizing from the limbic system to the sensorimotor cortex.

Regional excitatory and inhibitory amino acid concentrations in Noda epileptic rat (NER) brain.

We measured regional concentrations of excitatory and inhibitory amino acids in Noda epileptic rat (NER) brains to investigate the mechanisms responsible for spontaneous generalized seizures. Compared with Fisher 344 (F344) rats and F1 hybrid (female NER x male F344 rat) rats, NERs had significantly higher concentrations of glycine in the cerebellum. NERs and F1 hybrid rats had significantly lower concentrations of taurine in the cerebellum than did F344 rats. Although our findings do not explain sufficiently the mechanisms directly responsible for spontaneous seizures, they suggest that the cerebellum of NER may be in an excited state to dampen seizures, while the cerebellum of F1 hybrid rats may also be slightly excited to inhibit milder forms of seizures. Further studies, including microdialysis and receptor binding assays, will be required to elucidate these mechanisms.

Abnormality of Ca2+ Channels in CA3 Pyramidal Neurons of Noda Epileptic Rats (NERs)

Purpose: The Noda epileptic rat (NER), which was found in a colony of Crj‐Wistar rats, shows spontaneous tonic‐clonic convulsions. After 8–16 weeks of age, a long‐lasting depolarization shift accompanied by repetitive firing is observed in the CA3 pyramidal neurons of the hippocampus in NERs with seizures. This electrophysiologic study using hippocampal slice preparations from NERs was performed to determine whether this abnormal firing in CA3 neurons developed with age. and its probable relationship with the abnormality of Ca2+ channels was investigated pharmacologically.

Reproductive and developmental toxicity screening test of tetrahydrofurfuryl alcohol in rats

Twelve male and female rats per group were given tetrahydrofurfuryl alcohol (THFA) by gavage at 0, 15, 50, 150 or 500 mg/kg/day. Males were dosed for 47 days, beginning 14 days before mating, and females were dosed for 42-52 days beginning 14 days before mating to day 4 of lactation throughout the mating and gestation period. Changes in locomotor activity, inhibition of body weight gain, and/or histopathological changes in the thymus, spleen, testes and/or epididymides were observed in males and females at 150 mg/kg and above. No effects of THFA were found on the copulation index, fertility index, or the number of corpora lutea and implantations in pregnant females. At 500 mg/kg, no pregnant females delivered any pups. At 150 mg/kg, gestation length was prolonged, and the total number of pups born and the number of live pups on postnatal days 0 and 4 was markedly decreased. No effects of THFA were found on the sex ratio and body weight of live pups, or the incidence of pups with malformations or variations. Based on these findings, the NOAELs for parental and reproductive/developmental toxicity of THFA were concluded to be 50mg/kg/day in rats.

Effects of conventional anticonvulsant drugs on generalized tonic-clonic seizures in Noda epileptic rats

Noda epileptic rats (NERs) present with clinico-pathological manifestations reminiscent of human generalized tonic-clonic epilepsy. Thus, this strain of rat has been a model of primary, generalized, tonic-clonic epilepsy. However, the infrequency of seizures in these rats makes the assessment of antiepileptic drugs (AEDs) difficult. Therefore, traditional AEDs have only been tested in NERs against audiogenic seizures evoked by weekly acoustic priming from 3 to 22 weeks of age or by using the kindling procedure in adult animals. Adult NERs are susceptible to changes in their environment, such as bedding replacement or unpleasant sensory stimuli. In the present study, traditional AEDs-phenobarbital (PB) and sodium valproate (VPA)-were evaluated against seizures evoked by strong environmental stimuli in mature NERs that had not been previously primed. The number of animals presenting with seizures decreased in a dose-dependent manner following administration of either PB (dose range 1.0-5.0mg/kg) or VPA (50 and 100mg/kg). Consequently, the utility of NERs as a model of generalized tonic-clonic epilepsy was confirmed. This type of protocol can be used to further evaluate AEDs and test effects of chronic administration of AEDs.

Abnormal Excitability of Hippocampal CA3 Neurons in Noda Epileptic Rat (NER): Alteration of Seizure with Aging

Purpose: Noda epileptic rat (NER), a mutant found in thc colony of Crj:Wistar rats, spontaneously shows tonic‐clonic convulsions approximately once every 30 hours from 8–16 weeks of age. A long‐lasting dcpolarization shift accompanied by repetitivc firings are observed in hippocampal CA3 pyramidal neurons of NER with seizures. Using hippocampal slice preparations of NER, the present electrophysiologi‐ cal study was performed to elucidate whether this abnormal firing in CA3 neurons developed with age and if abnormality of Ca2+ channel was involved.

Age-dependent abnormal excitability of hippocampal CA3 neurons of noda epileptic rats (NER)

The Mongolian gerbil (Meriones unguiculatus) is a genetic animal model of epilepsy. In a seizure-sensitive strain that we have established, posture change, a potent seizure-inducer in adults, induces rhythmical backward movement of the pinnae in young animals. A major stimulus during posture change is vestibular; the vestibular cortex was localized in the somatosensory area and electrical stimulation of this site induced backward movement of the pinnae. Since this site may be involved in seizure, we studied its electrophysiological characteristics, using a telemetry machine. A puff of air was found to induce a sharp EEG wave in the region that includes the vestibular cortex; this effect and the movement of the pinnae were often repeated on stimulus cessation. Animals that had not undergone surgery also showed repetitive ear movement under similar conditions, suggesting that these electrophysiological features do no result from surgery, but are intrinsic to this strain.