Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, United States.
Neurotoxicology. 2012 Jun;33(3):500-11. doi: 10.1016/j.neuro.2012.02.010. Epub 2012 Feb 24.
The occurrence of status epilepticus (SE) is considered the main cause of brain lesions and morphological alterations, such as hippocampal neuron loss, that result in chronic epilepsy. Previous work demonstrated the convulsive and widespread neuropathological effects of soman, an organophosphorus compound that causes SE and severe recurrent seizures as a result of exposure. Seizures begin rapidly after exposure, can continue for hours, and contribute to prolonged physical incapacitation of the victim. This study attempts to identify anticonvulsive and neuroprotective drugs against soman exposure. Male Sprague-Dawley rats were exposed to 1.0 LD(50) soman. EEGraphical and neuropathological (Fluoro-Jade B staining) effects were analyzed at 72 h post-exposure to soman and subsequent treatments with diazepam (DZP) alone or in combination with histone deacetylase inhibitors, suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). The extent of brain damage was dependent on the length of SE and not on the number of recurrent seizures. DZP treatment alone decreased SE time and damage in hippocampus, amygdala, thalamus and cortex, but not in piriform nuclei. The combination of DZP and VPA 100 mg/kg showed more anticonvulsive effects, decreased SE time, and afforded more neuroprotection in the hippocampus, mainly the ventral portion. The combination DZP and SAHA 25 mg/kg was more neuroprotective, but not more anticonvulsant than DZP alone. The DZP combination with VPA HDAC inhibitor proved to be a good treatment for SE and neuronal damage caused by soman exposure.
癫痫持续状态（SE）的发生被认为是脑损伤和形态改变的主要原因，如海马神经元丢失，导致慢性癫痫。先前的工作表明，有机磷化合物梭曼会引起惊厥和广泛的神经病理学效应，导致 SE 和严重的反复发作性癫痫。癫痫发作在暴露后迅速开始，可以持续数小时，并导致受害者长期身体残疾。本研究试图确定对抗梭曼暴露的抗惊厥和神经保护药物。雄性 Sprague-Dawley 大鼠暴露于 1.0 LD(50) 梭曼。在暴露于梭曼后 72 小时，分析脑电图和神经病理学（荧光黄 B 染色）效应，随后单独用地西泮（DZP）或联合组蛋白去乙酰化酶抑制剂，丁酸钠（SAHA）或丙戊酸钠（VPA）治疗。脑损伤的程度取决于 SE 的持续时间，而与反复发作性癫痫的次数无关。DZP 单独治疗可减少 SE 时间和海马、杏仁核、丘脑和皮质的损伤，但对梨状核无影响。DZP 与 VPA 100 mg/kg 联合具有更强的抗惊厥作用，可减少 SE 时间，并在海马体（主要是腹侧部分）提供更多的神经保护作用。DZP 与 SAHA 25 mg/kg 联合比 DZP 单独治疗更具神经保护作用，但抗惊厥作用不更强。DZP 与 VPA HDAC 抑制剂联合治疗被证明是治疗 SE 和梭曼暴露引起的神经元损伤的有效方法。
