Repeated low-dose treatment of rats with pilocarpine:: low mortality but high proportion of rats developing epilepsy
Repeated low-dose treatment of rats with pilocarpine:: low mortality but high proportion of rats developing epilepsy
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DOI：
10.1016/s0920-1211(01)00272-8
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发表时间：
2001-08-01
影响因子：
2.2
通讯作者：
Löscher, W
中科院分区：
文献类型：
--
作者：
Glien, M;Brandt, C;Löscher, W
大鼠全身给予毛果芸香碱可导致类似于人类颞叶癫痫的慢性行为状态。毛果芸香碱癫痫模型广泛用于研究癫痫持续状态 (SE) 导致癫痫发生的因素。为此，毛果芸香碱可以单独以高全身剂量给药，也可以与锂联合给药，锂可显着增强毛果芸香碱的惊厥作用。然而，这两种实验方案都与高死亡率相关。在本研究中，我们评估了重复给予低剂量的毛果芸香碱是否可以降低大鼠的死亡率。地西泮限制了大鼠在 SE 中度过的时间。在不含锂的大鼠中进行的初步实验表明，与单次高剂量给药相比，重复低剂量给药毛果芸香碱过于耗时，无法产生SE。所有后续实验均在经过锂预处理的大鼠中进行。单剂量注射 30 mg/kg 毛果芸香碱，约 70% 的动物产生 SE，但尽管 90 分钟后用地西泮中断 SE，仍有 45% 的大鼠死亡。重复腹腔注射以 30 分钟间隔给予 10 mg/kg 毛果芸香碱，注射 2-4 次后导致 SE，诱导 SE 所需的毛果芸香碱平均剂量为 26 mg/kg。当SE在90分钟后中断时，死亡率低于10%，与单次给予30 mg/kg毛果芸香碱的方案相比显着降低。与死亡率相反，自发性复发性癫痫发作的发展在实验方案之间没有差异。几乎所有经历过至少 60 分钟 SE 的大鼠都发展为慢性癫痫。第一次自发性癫痫发作的平均潜伏期约为 40 天。尽管与单剂量给药相比，重复低剂量治疗的动物组自发性癫痫发作的频率往往更高，但不同方案之间自发性癫痫发作的频率和严重程度没有显着差异。本研究表明，用几种低剂量的毛果芸香碱对经过锂预处理的大鼠进行全身治疗，可以有效地产生 SE 和慢性癫痫，且死亡率比单剂量毛果芸香碱低得多。 (C) 2001 Elsevier Science B.V. 保留所有权利。
Systemic administration of pilocarpine in rats can result in a chronic behavioral state that is similar to human temporal lobe epilepsy. The pilocarpine model of epilepsy is widely used for studying the factors that contribute to the development of epilepsy as a consequence of status epilepticus (SE). For this purpose, pilocarpine is either administered alone at a high systemic dose or in combination with lithium, which markedly potentiates the convulsant effect of pilocarpine. Both experimental protocols, however, are associated with high mortality rates. In the present study, we evaluated whether mortality rate in rats can be decreased by repeated administration of low doses of pilocarpine. The time the rats spent in SE was limited by diazepam. Preliminary experiments in lithium-free rats indicated that repeated low-dose administration of pilocarpine is too time-consuming to produce SE compared to single high-dose administration. All subsequent experiments were performed in lithium-pretreated rats. Single-dose injection of 30 mg/kg pilocarpine produced SE in approximately 70% of the animals, but 45% of the rats died although SE was interrupted by diazepam after 90 min. Repeated i.p. administration of 10 mg/kg pilocarpine at 30-min intervals resulted in SE after 2-4 injections, the mean dose of pilocarpine needed to induce SE was 26 mg/kg. When SE was interrupted after 90 min, mortality rate was below 10%, which was significantly lower compared to the protocol with one single administration of 30 mg/kg pilocarpine. In contrast to mortality rate, the development of spontaneous recurrent seizures did not differ between experimental protocols. Almost all rats which had experienced a SE of at least 60 min developed chronic epilepsy. Average latency to the first spontaneous seizure was approximately 40 days. The frequency and severity of spontaneous seizures was not significantly different between protocols, although animal groups with repeated low-dose treatment tended to have higher frequencies of spontaneous seizures compared to single-dose administration. The present study demonstrates that systemic treatment of lithium-pretreated rats with several low doses of pilocarpine efficiently produces SE and chronic epilepsy with much lower mortality rates than single-dose pilocarpine. (C) 2001 Elsevier Science B.V. All rights reserved.