title: Dual Therapeutic Effects of C-10068, a Dextromethorphan Derivative, Against Post-Traumatic Nonconvulsive Seizures and Neuroinflammation in a Rat Model of Penetrating Ballistic-Like Brain Injury.
abstract: Post-traumatic seizures can exacerbate injurious outcomes of severe brain trauma, yet effective treatments are limited owing to the complexity of the pathology underlying the concomitant occurrence of both events. In this study, we tested C-10068, a novel deuterium-containing analog of (+)-N-methyl-3-ethoxymorphinan, in a rat model of penetrating ballistic-like brain injury (PBBI) and evaluated the effects of C-10068 on PBBI-induced nonconvulsive seizures (NCS), acute neuroinflammation, and neurofunctional outcomes. NCS were detected by electroencephalographic monitoring. Neuroinflammation was evaluated by immunohistochemical markers, for example, glial fibrillary acidic protein and major histocompatibility complex class I, for activation of astrocytes and microglia, respectively. Neurofunction was tested using rotarod and Morris water maze tasks. Three infusion doses of C-10068 (1.0, 2.5, and 5.0 mg/kg/h × 72 h) were tested in the antiseizure study. Neuroinflammation and neurofunction were evaluated in animals treated with 5.0 mg/kg/h × 72 h C-10068. Compared to vehicle treatment, C-10068 dose dependently reduced PBBI-induced NCS incidence (40-50%), frequency (20-70%), and duration (30-82%). The most effective antiseizure dose of C-10068 (5.0 mg/kg/h × 72 h) also significantly attenuated hippocampal astrocyte activation and perilesional microglial reactivity post-PBBI. Within C-10068-treated animals, a positive correlation was observed in reduction in NCS frequency and reduction in hippocampal astrocyte activation. Further, C-10068 treatment significantly attenuated astrocyte activation in seizure-free animals. However, C-10068 failed to improve PBBI-induced motor and cognitive functions with the dosing regimen used in this study. Overall, the results indicating that C-10068 exerts both potent antiseizure and antiinflammatory effects are promising and warrant further investigation.
authors: 1 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors: Xi-Chun May
authors: XC
authors: Lu
authors: 1 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors: Deborah A
authors: DA
authors: Shear
authors: 2 Concert Pharmaceuticals Inc. , Lexington, Massachusetts.
authors: Philip B
authors: PB
authors: Graham
authors: 2 Concert Pharmaceuticals Inc. , Lexington, Massachusetts.
authors: Gary W
authors: GW
authors: Bridson
authors: 2 Concert Pharmaceuticals Inc. , Lexington, Massachusetts.
authors: Vinita
authors: V
authors: Uttamsingh
authors: 1 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors: Zhiyong
authors: Z
authors: Chen
authors: 1 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors: Lai Yee
authors: LY
authors: Leung
authors: 1 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors: Frank C
authors: FC
authors: Tortella
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003915:Dextromethorphan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D020197:Head Injuries, Penetrating / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D006624:Hippocampus / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D017628:Microglia / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology
chemical_list: D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D003915:Dextromethorphan
keywords: C-10068; EEG; dextromethorphan; neuroinflammation; nonconvulsive seizures; penetrating brain injury