Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure

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• 作者：Franco Rossetti^a ; Marcio de Araujo Furtado^a ; Thomas Pak^a ; Keenan Bailey^a ; Mallory Shields^a ; Soma Chanda^a ; Michael Addis^a ; Benjamin D. Robertson^a ; Mark Moffett^b ; Lucille A. Lumley^b ; Debra L. Yourick^a ; ^{debra.yourick@us.army.mil} ; ^{yourickd@verizon.net}
• 关键词：Suberoylanilide hydroxamic acid ; Valproic acid ; Fluoro-Jade B ; Hippocampus ; Amygdala ; Thalamus ; Piriform ; Cortex ; Soman
• 刊名：Neurotoxicology
• 出版年：2012
• 期刊代码：35_0161813x
• 类别：pha
• 出版时间：June, 2012
• 卷：33
• 期：3
• 页码：500-511
• 文件大小：2401 K

摘要

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 LD₅₀ 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.