自然発症てんかんラットの抗てんかん薬に対する反応性

Responsiveness of the spontaneously epileptic rat (SER), a double mutant, to antiepileptic drugs.

はじめに

　てんかん発作を起こす遺伝関係の明らかな動物モデルとしては，マウス類が知られている。けいれん発作を起こすものとしては，我が国で開発されたElマウス^10,30）をはじめ，quaking^5），epf^8），SpS^15），lurcher^28）マウスなどがあり，欠神様発作を起こすものとしてはtotteringマウス^12,19）などがある。ラットではけいれん発作を起こすものとして，genetically epilepsy-prone rat^11,21）が知られているが，これは遺伝関係がもう一つ明確ではなく，発作の程度も個体によってまちまちである。また欠神様発作を起こすラットも報告されているものの，老齢Wistar系ラットのコロニーに見出されているというだけで，遺伝関係は明らかでない。

　ところで，京都大学には1957年以来Wistar系ラットをKyo：Wistarと呼び，inbred colonyとして維持している。このコロニーにおいて，主として上半身に振せんを示す突然変異体が見出され，tremor rat（tm／tm）と命名された^34）。この動物も加齢とともに欠神様発作を示すことが認められている^26）。一方，西ドイツではSprague Dawley系ラットのコロニーより，主として下半身に振せんを示す突然変異体が見出されており，zitterrat（zi／zi）と命名されていた^20）。

The spontaneously epileptic rat (SER; zi/zi, tm/tm), a double mutant, was obtained by mating heterozygous tremor rat (tm/+), a mutant found in Kyo: Wistar colony, with homozygous zitter rat (zi/zi) found in Sprang Dawley colony in West Germany. The F₁, generation are all normal, whereas in the F₂ generation obtained by mating heterozygous rats for tremor and zitter (zi/+, tm/+), the ratio of normal type: zitter type: tremor type: SER is 9:3:3:1. Thereafter, SER are obtained at ratio of 1/4 by mating (zi/zi, tm/+). SER show whole body tremor and staggering gait as well as absence-like seizure and tonic convulsion characterized by the appearance of 5-7 Hz spike-wave-like complexes and low voltage fast waves in cortical and hippocampal EEG, respectively. Absence-like seizure was inhibited by trimethadione and ethosuximide, and tonic convulsion was by phenytoin and carbamazepine. Phenobarbital, valproate and diazepam inhibited both seizures. These results suggest that absence-like seizure and tonic convulsion seen in SER correspond, respectively, to petit mal and tonic-clonic seizures in man. When SER were continuously fed pellets containing 0.1% phenobarbital after 7 weeks of age, the plasma level of the drug remained at 30-70 μg/ml. Under these conditions, the phenobarbital-treated group showed an increase in body weight and longer survival, compared with the control group. Tonic convulsion was inhibited in phenobarbital-treated group, whole absence-like seizure was not affected, being in line with the effects of the drug in man. Therefore, SER is considered to be useful in evaluation of acute and chronic effects of antiepileptic drugs. TRH inhibited both absence-like seizure and tonic convulsion in SER, as noted in kindled animals. The effects of TRH on hippocampal CA3 pyramidal neurons were examined in SER and Wistar rat usingslice preparations. In SER, stimulation of mossy fibers produced population spike followed by a long-lasting depolarization shift in field recording and burst discharges in extracellular single neuron recording. Addition of TRH into the bath inhibited these depolarization shift and burst discharges in SER, but not population spike nor repetitive firing induced in Mg2+-free medium in extracellularly recorded single neurons of normal Wistar rat. However, burst of action potentials, which were sometimes obtained with intracellular recording in CA3 pyramidal neurons of normal Wistar rat, was inhibited by TRH. Therefore, TRH may inhibit hyperexcitability of CA3 pyramidal neurons, although the underlying mechanism should be examined. Thus, SER is also a useful model in studying the pathogenesis of epilepsy.