naa a22 4500 510799329 CHVBK 20180411083348.0 cr unu---uuuuu 180411e20130801xx s 000 0 eng 10.1007/s12028-012-9808-8 doi (NATIONALLICENCE)springer-10.1007/s12028-012-9808-8 Lacosamide Improves Outcome in a Murine Model of Traumatic Brain Injury [Elektronische Daten] [Bo Wang, Hana Dawson, Haichen Wang, Dawn Kernagis, Brad Kolls, Lucy Yao, Daniel Laskowitz] Background: Use of antiepileptic drugs (AED's) is common in the neurocritical care setting. However, there remains a great deal of controversy regarding the optimal agent. Studies associating the prophylactic use of AED's with poor outcomes are heavily biased by the prevalent use of phenytoin, an agent highly associated with deleterious effects. In the current study, we evaluate lacosamide for neuroprotective properties in a murine model of closed head injury. Methods: Mice were subjected to moderate closed head injury using a pneumatic impactor, and then treated with either low-dose (6mg/kg) or high-dose (30mg/kg) lacosamide or vehicle at 30min post-injury, and twice daily for 3days after injury. Motor and cognitive functional assessments were performed following injury using rotarod and Morris Water Maze, respectively. Neuronal injury and microglial activation were measured by flourojade-B, NeuN, and F4/80 staining at 1 and 7days post-injury. Timm's staining was also performed to assess lacosamide effects on mossy fiber axonal sprouting. To evaluate possible mechanisms of lacosamide effects on the inflammatory response to injury, an RNA expression array was used to evaluate for alterations in differential gene expression patterns in injured mice following lacosamide or vehicle treatments. Results: High-dose lacosamide was associated with improved functional outcome on both the rotarod and Morris Water Maze. High-dose lacosamide was also associated with a reduction of neuronal injury at 24h post-injury. However, the reduction in neuronal loss observed early did not result in greater neuronal density at 31days post-injury based on unbiased stereology of NeuN staining. High-dose lacosamide was also associated with a significant reduction in microglial activation at 7days post-injury. The therapeutic effects of lacosamide are associated with a delay in injury-related changes in RNA expression of a subset of inflammatory mediator genes typically seen at 24h post-injury. Conclusions: Administration of lacosamide improves functional performance, and reduces histological evidence of acute neuronal injury and neuroinflammation in a murine model of closed head injury. Lacosamide effects appear to be mediated via a reduction or delay in the acute inflammatory response to injury. Prior clinical and animal studies have found antiepileptic treatment following injury to be detrimental, though these studies are biased by the common use of older medications such as phenytoin. Our current results as well as prior work on levetiracetam suggest the newer AED's may be beneficial in the setting of acute brain injury. Springer Science+Business Media New York, 2012 Traumatic brain injury nationallicence Lacosamide nationallicence Neuroprotection nationallicence Inflammation nationallicence Microglial activation nationallicence Wang Bo Department of Anesthesiology, Shandong University Shandong Provincial Hospital, 324 Jingwu Road, 250021, Jinan, Shandong, People's Republic of China aut Dawson Hana Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut Wang Haichen Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut Kernagis Dawn Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut Kolls Brad Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut Yao Lucy Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut Laskowitz Daniel Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut Neurocritical Care Springer US; http://www.springer-ny.com 19/1(2013-08-01), 125-134 1541-6933 19:1<125 2013 19 12028 https://doi.org/10.1007/s12028-012-9808-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s12028-012-9808-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wang Bo Department of Anesthesiology, Shandong University Shandong Provincial Hospital, 324 Jingwu Road, 250021, Jinan, Shandong, People's Republic of China aut NATIONALLICENCE 700 1- Dawson Hana Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Wang Haichen Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Kernagis Dawn Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Kolls Brad Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Yao Lucy Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 700 1- Laskowitz Daniel Brain Injury Translation Research Center, Duke University Medical Center, 27710, Durham, NC, USA aut NATIONALLICENCE 773 0- Neurocritical Care Springer US; http://www.springer-ny.com 19/1(2013-08-01), 125-134 1541-6933 19:1<125 2013 19 12028 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer