Department of Anatomy, Physiology and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Br J Pharmacol. 2011 Nov;164(5):1495-505. doi: 10.1111/j.1476-5381.2011.01427.x.
Caramiphen is a muscarinic antagonist with potent anticonvulsant properties. Here, we investigated the efficacy of caramiphen against behavioural seizures and neuropathology induced by the nerve agent soman, and revealed two mechanisms that may underlie the anticonvulsant efficacy of caramiphen.
Rats were given caramiphen at 30 or 60 min after treatment with soman. Neuronal loss in the basolateral amygdala (BLA) and neuronal degeneration in the amygdala, hippocampus, piriform cortex, entorhinal cortex and neocortex, were investigated 24 h after soman, using design-based stereology and FluoroJade-C staining. The effects of caramiphen on NMDA-, AMPA- and GABA-evoked currents were studied in the BLA region of in vitro brain slices from un-treated rats, using whole-cell recordings.
Caramiphen given either 30 min or 60 min after soman, suppressed behavioural seizures within 10 min, but required 1∼4.5 h for complete cessation of seizures. Neuronal loss and degeneration were significantly reduced in the caramiphen-treated, soman-exposed rats. Postsynaptic currents evoked by puff-application of NMDA on BLA principal cells were reduced by caramiphen in a dose-dependent manner (100 µM, 300 µM and 1 mM), while GABA-evoked currents were facilitated by 100 µM and 300 µM, but depressed by 1 mM caramiphen. AMPA-evoked currents were not affected by caramiphen.
Caramiphen offered partial protection against soman-induced seizures and neuropathology, even when given 60 min after soman. NMDA receptor antagonism and facilitation of GABAergic inhibition in the BLA may play a key role in the anticonvulsive and neuroprotective properties of caramiphen.
卡米酚是一种具有强大抗惊厥特性的毒蕈碱拮抗剂。在这里，我们研究了卡米酚对梭曼诱导的行为性癫痫发作和神经病理学的疗效，并揭示了卡米酚抗惊厥疗效的两个可能机制。
在给予梭曼后 30 或 60 分钟，给大鼠给予卡米酚。在给予梭曼后 24 小时，使用基于设计的立体学和 FluoroJade-C 染色，研究了基底外侧杏仁核（BLA）中的神经元损失和杏仁核、海马、梨状皮层、内嗅皮层和新皮层中的神经元变性。使用全细胞膜片钳记录，在未经处理的大鼠脑切片的 BLA 区域研究了卡米酚对 NMDA、AMPA 和 GABA 诱发电流的影响。
给予卡米酚后 30 分钟或 60 分钟，可在 10 分钟内抑制行为性癫痫发作，但需要 1∼4.5 小时才能完全停止癫痫发作。在卡米酚治疗、梭曼暴露的大鼠中，神经元损失和变性明显减少。BLA 主细胞上 NMDA 脉冲应用诱发的突触后电流被卡米酚剂量依赖性地降低（100µM、300µM 和 1mM），而 GABA 诱发的电流被 100µM 和 300µM 促进，但被 1mM 卡米酚抑制。AMPA 诱发的电流不受卡米酚影响。
即使在给予梭曼后 60 分钟，卡米酚也能提供部分梭曼诱导的癫痫发作和神经病理学保护。BLA 中的 NMDA 受体拮抗和 GABA 能抑制的促进可能在卡米酚的抗惊厥和神经保护特性中发挥关键作用。
