lacosamide and Brain-Injuries

In neonates supraphysiological oxygen therapy has been demonstrated to cause neuronal death in hippocampus, prefrontal cortex, parietal cortex, and retrosplenial cortex. There is a need for the detection of novel neuroprotective drugs. Neuroprotective effects of lacosamide or memantine have been demonstrated in adult patients with ischemia, trauma and status epilepticus. The effects in immature brains may be different. This study aimed to evaluate neuroprotective effects of lacosamide and memantine treatment in a hyperoxia-induced brain injury model in immature rats. This study was performed in the Animal Experiments Laboratory of Dokuz Eylul University Faculty of Medicine. Neonatal Wistar strain rat pups were exposed to hyperoxia (80% oxygen + 20% nitrogen) for five days postnatally. They were divided into five groups; hyperoxia + lacosamide, hyperoxia + memantine, hyperoxia + lacosamide and memantine, hyperoxia + saline, control groups. After termination of the experiment, brain tissues were examined. Neuron counting in examined regions were found to be higher in hyperoxia + memantine and hyperoxia + lacosamide and memantine groups than hyperoxia + saline group. The presence of apoptotic cells evaluated with TUNEL and active Caspase-3 in hyperoxia + memantine and hyperoxia + lacosamide and memantine groups were found to be lower compared to hyperoxia + saline group. This study demonstrates that neuron death and apoptosis in newborn rat brains after hyperoxia is reduced upon memantine treatment. This is the first study to show the effects of memantine and lacosamide on hyperoxia-induced damage in neonatal rat brains.

Topics: Animals; Animals, Newborn; Apoptosis; Brain; Brain Injuries; Hyperoxia; Lacosamide; Memantine; Neurons; Neuroprotective Agents; Rats, Wistar

In a subgroup of patients, traumatic brain injury (TBI) results in the occurrence of acute epileptic seizures or even status epilepticus, which are treated with antiepileptic drugs (AEDs). Recent experimental data, however, suggest that administration of AEDs at the early post-injury phase can compromise the recovery process. The present study was designed to assess the profile of a novel anticonvulsant, lacosamide (Vimpat) on post-TBI structural, motor and cognitive outcomes. Moderate TBI was induced by lateral fluid-percussion injury in adult rats. Treatment with 0.9% saline or lacosamide (30 mg/kg, i.p.) was started at 30 min post-injury and continued at 8h intervals for 3d (total daily dose 90 mg/kg/d). Rats were randomly assigned to 4 treatment groups: sham-operated controls treated with vehicle (Sham-Veh) or lacosamide (Sham-LCM) and injured animals treated with vehicle (TBI-Veh) or lacosamide (TBI-LCM). As functional outcomes we tested motor recovery with composite neuroscore and beam-walking at 2, 7, and 15 d post-injury. Cognitive recovery was tested with the Morris water-maze at 12-14 d post-TBI. To assess the structural outcome, animals underwent magnetic resonance imaging (MRI) at 2 d post-TBI. At 16d post-TBI, rats were perfused for histology to analyze cortical and hippocampal neurodegeneration and axonal damage. Our data show that at 2 d post-TBI, both the TBI-Veh and TBI-LCM groups were equally impaired in neuroscore. Thereafter, motor recovery occurred similarly during the first week. At 2 wk post-TBI, recovery of the TBI-LCM group lagged behind that in the TBI-VEH group (p<0.05). Performance in beam-walking did not differ between the TBI-Veh and TBI-LCM groups. Both TBI groups were similarly impaired in the Morris water-maze at 2 wk post-TBI. MRI and histology did not reveal any differences in the cortical or hippocampal damage between the TBI-Veh and TBI-LCM groups. Taken together, acute treatment with LCM had no protective effects on post-TBI structural or functional impairment. Composite neuroscore in the TBI-LCM group lagged behind that in the TBI-Veh group at 15 d post-injury, but no compromise was found in other indices of post-TBI recovery in the LCM treated animals.

Topics: Acetamides; Animals; Anticonvulsants; Brain; Brain Injuries; Disease Models, Animal; Lacosamide; Male; Maze Learning; Rats; Rats, Sprague-Dawley; Recovery of Function

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.. Mice were subjected to moderate closed head injury using a pneumatic impactor, and then treated with either low-dose (6 mg/kg) or high-dose (30 mg/kg) lacosamide or vehicle at 30 min post-injury, and twice daily for 3 days 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 7 days 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.. 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 24 h post-injury. However, the reduction in neuronal loss observed early did not result in greater neuronal density at 31 days post-injury based on unbiased stereology of NeuN staining. High-dose lacosamide was also associated with a significant reduction in microglial activation at 7 days 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 24 h post-injury.. 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.

Topics: Acetamides; Animals; Anticonvulsants; Brain Injuries; Disease Models, Animal; Encephalitis; Head Injuries, Closed; Lacosamide; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Recovery of Function; Transcriptome; Treatment Outcome