J Clin Neurol.  2017 Apr;13(2):138-143. 10.3988/jcn.2017.13.2.138.

Neuroprotective Effect of Lacosamide on Hypoxic-Ischemic Brain Injury in Neonatal Rats

• Kim GH
• Byeon JH
• Eun BL

• KMID: 2376014
• DOI: http://doi.org/10.3988/jcn.2017.13.2.138

Abstract

BACKGROUND AND PURPOSE
Lacosamide (LCM) is an antiepileptic drug that enhances the slow inactivation of sodium channels and modulates collapsin response mediator protein-2. LCM was recently demonstrated to exert a neuroprotective effect in a murine model of traumatic brain injury and status epilepticus. Assuming the same underlying excitotoxicity-related brain injury mechanism, we hypothesized that LCM would have a neuroprotective effect in hypoxic-ischemic brain injury.
METHODS
We divided rats into three groups at each testing session: pre- or postfed with LCM, fed with normal saline, and sham. A hypoxic-ischemic brain injury was induced by subjecting 7-day-old rats to right carotid artery coagulation followed by 2.5 h of exposure to 8% oxygen. The animals were killed on postnatal day 12 to evaluate the severity of brain damage. Open field testing was also performed between week 2 and week 6, and the Morris water maze test was performed in week 7 after hypoxia-ischemia.
RESULTS
The incidence of liquefactive cerebral infarction was lower in rats prefed with LCM at 100 mg/kg/dose, with the mortality rate being higher at higher doses (200 and 300 mg/kg/dose). The infarct areas were smaller in LCM-prefed rats in several brain regions including the hemisphere, hippocampus, cortex, and striatum. Spatial learning and memory function were better in LCM-prefed rats (p<0.05). No effect was observed in postfed rats.
CONCLUSIONS
This study suggests that LCM pretreatment exerts a neuroprotective effect on hypoxia-ischemia in neonatal rats. The obtained results suggest that LCM pretreatment could be used as an effective neuroprotective method for neonates under hypoxic-ischemic conditions including heart surgery.

Keyword

brain; hypoxia-ischemia; lacosamide; neuroprotection; newborn; rat

MeSH Terms

Animals
Brain Injuries*
Brain*
Carotid Arteries
Cerebral Infarction
Hippocampus
Humans
Incidence
Infant, Newborn
Memory
Methods
Mortality
Neuroprotection
Neuroprotective Agents*
Oxygen
Rats*
Semaphorin-3A
Sodium Channels
Spatial Learning
Status Epilepticus
Thoracic Surgery
Water
Neuroprotective Agents
Oxygen
Semaphorin-3A
Sodium Channels
Water

Figure

• 

  Fig. 1 Example images of the rat brain. Left image shows brain tissue loss, while the brain is intact in the right image.

• 

  Fig. 2 Quantification of infarct areas after lacosamide (LCM) pretreatment at 100 mg/kg/dose. The mean percentage of right-side damage relative to the intact left side. Pretreatment with LCM at 100 mg/kg/dose (n=16) significantly decreased the infarcted areas in several brain regions (including the hemisphere, hippocampus, cortex, and striatum) relative to the normal-saline-treated group (NS; n=10). *p<0.05.

• 

  Fig. 3 Open field activities test. Three groups were included in the open field activities test from week 2 to week 7 following hypoxia-ischemia: sham (n=14), normal-saline-treated (NS; n=16), and LCM-pretreated (100 mg/kg/dose, n=22) groups. No difference was found in exploratory behavior between the LCM-pretreatment group (100 mg/kg/dose) and the control group, suggesting that neither hypoxia-ischemia nor LCM affected exploratory activity. Data are mean and SEM values. LCM: lacosamide.

• 

  Fig. 4 Morris water maze test. Three groups were included in the Morris water maze test: sham (n=14), normal-saline-treated (NS; n=16), and LCM-pretreated (100 mg/kg/dose, n=22) 8-week-old rats. The mean escape latency was shorter in the LCM-pretreatment group than in the NS, which implies better spatial memory function in the LCM-pretreatment group. Data are mean and SEM values. *p<0.05. LCM: lacosamide.

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