Hillert Markus H, Imran Imran, Zimmermann Martina, Lau Helene, Weinfurter Stefanie, Klein Jochen
Department of Pharmacology, School of Pharmacy, Biocenter N260, Goethe University Frankfurt, Frankfurt am Main, Germany.
J Neurochem. 2014 Oct;131(1):42-52. doi: 10.1111/jnc.12787. Epub 2014 Jun 23.
The lithium-pilocarpine model is a rat model of epilepsy that mimics status epilepticus in humans. Here, we report changes of acetylcholine (ACh) release in the hippocampus before, during and after status epilepticus as monitored by microdialysis in unanesthetized rats. Administration of pilocarpine (30 mg/kg s.c.) to rats pretreated with lithium chloride (127 mg/kg i.p.) caused a massive, six-fold increase of hippocampal ACh release, paralleling the development of tonic seizures. When seizures were stopped by administration of diazepam (10 mg/kg i.p.) or ketamine (75 mg/kg i.p.), ACh levels returned to normal. Extracellular concentrations of glutamate remained unchanged during this procedure. Administration of atropine (1 mg/kg i.p.) 2 h after pilocarpine caused a further increase of ACh but did not affect seizures, whereas injection of mecamylamine (5 mg/kg i.p.) reduced ACh levels and seizures in a delayed fashion. Local infusion of tetrodotoxin, 1 μM locally) or hemicholinium (10 μM locally) strongly reduced ACh release and had delayed effects on seizures. Administration of glucose or inositol (250 mg/kg each i.p.) had no visible consequences. In parallel experiments, lithium-pilocarpine-induced status epilepticus also enhanced striatal ACh release, and hippocampal ACh levels equally increased when status epilepticus was induced by kainate (30 mg/kg i.p.). Taken together, our results demonstrate that seizure development in status epilepticus models is accompanied by massive increases of extracellular ACh, but not glutamate, levels. Treatments that reduce seizure activity also reliably reduce extracellular ACh levels.
锂-毛果芸香碱模型是一种模拟人类癫痫持续状态的大鼠癫痫模型。在此，我们报告了在未麻醉大鼠中通过微透析监测癫痫持续状态发作前、发作期间和发作后海马中乙酰胆碱（ACh）释放的变化。给预先腹腔注射氯化锂（127 mg/kg）的大鼠皮下注射毛果芸香碱（30 mg/kg）会导致海马ACh释放量大幅增加6倍，这与强直发作的发展情况平行。当通过腹腔注射地西泮（10 mg/kg）或氯胺酮（75 mg/kg）停止发作时，ACh水平恢复正常。在此过程中谷氨酸的细胞外浓度保持不变。毛果芸香碱注射2小时后腹腔注射阿托品（1 mg/kg）会使ACh进一步增加，但不影响发作，而注射美加明（5 mg/kg腹腔注射）会延迟降低ACh水平和发作。局部输注河豚毒素（1 μM局部）或半胱氨酸（10 μM局部）会强烈降低ACh释放，并对发作有延迟影响。腹腔注射葡萄糖或肌醇（各250 mg/kg）没有明显影响。在平行实验中，锂-毛果芸香碱诱导的癫痫持续状态也会增强纹状体ACh释放，当通过腹腔注射海藻酸（30 mg/kg）诱导癫痫持续状态时，海马ACh水平同样会增加。综上所述，我们的结果表明，癫痫持续状态模型中的发作发展伴随着细胞外ACh水平的大幅增加，而不是谷氨酸水平的增加。降低发作活动的治疗方法也能可靠地降低细胞外ACh水平。
