title: Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure.
abstract: 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.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, United States.
authors.forename: Franco
authors.initials: F
authors.lastname: Rossetti
authors.forename: Marcio
authors.initials: M
authors.lastname: de Araujo Furtado
authors.forename: Thomas
authors.initials: T
authors.lastname: Pak
authors.forename: Keenan
authors.initials: K
authors.lastname: Bailey
authors.forename: Mallory
authors.initials: M
authors.lastname: Shields
authors.forename: Soma
authors.initials: S
authors.lastname: Chanda
authors.forename: Michael
authors.initials: M
authors.lastname: Addis
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Robertson
authors.forename: Mark
authors.initials: M
authors.lastname: Moffett
authors.forename: Lucille A
authors.initials: LA
authors.lastname: Lumley
authors.forename: Debra L
authors.initials: DL
authors.lastname: Yourick
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping / Q000379:methods; D058256:Brain Waves / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D019610:Cytoprotection; D003975:Diazepam / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012999:Soman / Q000633:toxicity*; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D000077337:Vorinostat; D014635:Valproic Acid; D012999:Soman; D003975:Diazepam