ホパンテン酸カルシウムのラット扁桃核キンドリングに対する促進効果

FACILITATORY EFFECT OF CALCIUM HOPANTENATE ON AMYGDALOID KINDLING IN RATS

　抄録　ラットの扁桃核キンドリングを用いて，ホパンテン酸（HOPA）カルシウム（HOPA-Ca）の全身けいれん誘発閾値（GST）とキンドリング形成過程に及ぼす影響について検討した。その結果は次の通りであった。（i） GSTに及ぼす影響：HOPA-Ca （50,100,250,500mg／kg, i．　p．）をGST刺激の1時間前に投与したところ，投与量に依存することなく，GSTの低下が認められた。HOPAそのものについても同様の検討を行ったところ，ほぼ同様の結果が得られた。このことから，HOPA-CaのGST低下作用にはHOPA独自の中枢作用が関与すると考えられる。（ii）キンドリング形成過程に及ぼす影響：HOPA-Ca（250mg／kg, i．　p．）を毎日，電気刺激の1時間前に投与したところ，キンドリング形成は対照群に比し有意に促進された（P＜0.05）。本研究の結果から，HOPA上CaはHOPAそのものの中枢作用が関与して扁桃核キンドリングに促進性に作用することが示唆される。従って，てんかんの既往のある者，その可能性のある者に対してはHOPA上Caの投与を控えるなどの慎重な配慮が求められよう。

Calcium hopantenate (HOPA-Ca), which is obtained by substituting the β-alanine of panto-thenic acid for γ-amino butyric acid (GABA), is a therapeutic drug for mental retardation and cere-brovascular dementia. HOPA-Ca is known to pro-duce convulsive seizures in some patients although it is also true that this improves EEG abnormalities and suppresses epileptic seizures. Thus, clinical observations suggest that HOPA-Ca exerts a para-doxical influence on epilepsy. In order to gain further insight into the influence of HOPA-Ca on epilepsy, we examined its effects on the genera-liezd seizure-triggering threshold (GST) of kindled amygdaloid (AM) seizure and on the rate of AM kindling in rats.

Male Wistar rats weighing 200-250 g were used.Under pentobarbital anesthesia, a bipolar elect-rode, made of twisted stainless steel wire 0.2 mm in diameter, was sterotaxically implanted into the left AM. Daily electrical stimulation was given at the intensity of afterdischarge threshold (ADT). Elect-rical stimilation was continued until at least five consecutive generalized convulsions were evoked. Subsequenty, the stimulus intensity was daily low-ered by 20-μA steps and the last stimulus intensity for evoking generalized convulsion was designated as the GST.

Experiment 1. Influence of HOPA-Ca on the GST ; HOPA-Ca was dissolved in saline as a vehicle. Injections of 50, 100, 250, 500 mg/kg HOPA-Ca were given intraperitoneally 60 min be-fore the stimulation at the GST. The GST never changed with vehicle injection. The GST increase was never observed with any amount of HOPA-Ca. However, the GST dropped following HOPA-Ca injection independent of its amount. The GST reduction was always 20-μA. HOPA alone was also tested in the same manner to exclude the in-fluence of Ca. Similar results were obtained. Therefore, the GST reduction induced by HOPA-Ca appeaers to be due to the unique central action of HOPA itself.

Experiment 2. Influence of HOPA-Ca on kind-ling rate ; Since the GST reduction following HOPA-Ca injection was non-dose-dependent, 250 mg/kg was arbitrarily employed in this experment. HOPA-Ca was daily given (i. p.) 60 min before electrical stimulation. This treatment significantly facilitated seizure development compared to con-trols (P<0.05).

The results of this study suggest that HOPA-Ca exerts facilitatory influence on AM kindling due to the unique central action of HOPA itself. This is in striking contrast to that of the previous studies, in which HOPA-Ca suppresses convulsive seizures and/or epileptic discharges induced by various type of chemicals or electroshock. The most likely explanation for the discrepancy between this study and previous ones may be due to the difference of animal models. That is, chronic epilepsy mode of AM kindling was employed in this study but acute convulsive seizure models in the previous stu-dies. Recently, Ogawa et al (1984) have reported that HOPA-Ca may behave as a mixed agonist-antagonist for GABA receptors in the brain. There-fore, when we focus the action of HOPA-Ca on GABA receptors, it is postulated that HOPA-Ca may act as an agonist in acute convulsive seizure models but as an antagonist in chronic epilepsy mo-del of AM kindling. At any rate, HOPA-Ca must be carefully used in patients with epilepsy or those with the possibility of it.