Markowitz Geoffrey J, Kadam Shilpa D, Smith Dani R, Johnston Michael V, Comi Anne M
Dept. of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Dept. of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neuroscience, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Dept. of Neurology, Johns Hopkins Medicine, Baltimore, MD 21205, USA.
Epilepsy Res. 2011 May;94(3):138-48. doi: 10.1016/j.eplepsyres.2011.01.002. Epub 2011 Apr 9.
Neonatal stroke presents with seizures that are usually treated with phenobarbital. We hypothesized that anticonvulsants would attenuate ischemic injury, but that the dose-dependent effects of standard anticonvulsants would impact important age-dependent and injury-dependent consequences. In this study, ischemia induced by unilateral carotid ligation in postnatal day 12 (P12) CD1 mice was immediately followed by an i.p. dose of vehicle, low-dose or high-dose phenobarbital. Severity of acute behavioral seizures was scored. 5-Bromo-2'-deoxyuridine (BrdU) was administered from P18 to P20, behavioral testing performed, and mice perfused at P40. Atrophy quantification and counts of BrdU/NeuN-labeled cells in the dentate gyrus were performed. Blood phenobarbital concentrations were measured. 30mg/kg phenobarbital reduced acute seizures and chronic brain injury, and restored normal weight gain and exploratory behavior. By comparison, 60mg/kg was a less efficacious anticonvulsant, was not neuroprotective, did not restore normal weight gain, and impaired behavioral and cognitive recovery. Hippocampal neurogenesis was not different between treatment groups. These results suggest a protective effect of lower-dose phenobarbital, but a lack of this effect at higher concentrations after stroke in P12 mice.
新生儿中风常伴有癫痫发作，通常用苯巴比妥进行治疗。我们推测抗惊厥药物会减轻缺血性损伤，但标准抗惊厥药物的剂量依赖性效应会影响重要的年龄依赖性和损伤依赖性后果。在本研究中，对出生后第12天（P12）的CD1小鼠进行单侧颈动脉结扎诱导缺血后，立即腹腔注射赋形剂、低剂量或高剂量的苯巴比妥。对急性行为性癫痫发作的严重程度进行评分。从P18至P20给予5-溴-2'-脱氧尿苷（BrdU），进行行为测试，并在P40对小鼠进行灌注。对齿状回进行萎缩定量分析以及BrdU/NeuN标记细胞计数。测量血液中苯巴比妥的浓度。30mg/kg的苯巴比妥可减轻急性癫痫发作和慢性脑损伤，并恢复正常体重增加和探索行为。相比之下，60mg/kg的苯巴比妥作为抗惊厥药物效果较差，没有神经保护作用，不能恢复正常体重增加，且会损害行为和认知恢复。各治疗组之间海马神经发生情况无差异。这些结果表明，较低剂量的苯巴比妥具有保护作用，但在P12小鼠中风后，较高浓度的苯巴比妥则缺乏这种作用。
