Trandafir C C, Pouliot W A, Dudek F E, Ekstrand J J
Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
Neuroscience. 2015 Jan 22;284:601-610. doi: 10.1016/j.neuroscience.2014.10.021. Epub 2014 Oct 18.
Seizures during status epilepticus (SE) cause neuronal death and induce cyclooxygenase-2 (COX-2). Pilocarpine-induced SE was used to determine if COX-2 inhibition with NS-398, when administered alone or with diazepam, decreases the duration and/or intensity of SE and/or reduces neuronal injury in the rat hippocampus.
Electroencephalogram (EEG) electrodes were implanted in male Sprague-Dawley rats. SE was induced with lithium-pilocarpine, and continuous EEG and video monitoring were performed for 24 h. Rats were divided into four groups (n=8-14 rats/group) and received NS-398, diazepam, NS-398 and diazepam, or vehicle 30 min after the first motor seizure. Six hours later, NS-398 injection was repeated in the NS-398 and in the NS-398+diazepam groups. The duration of SE (continuous spiking) and the EEG power in the γ-band were analyzed. FluoroJade B staining in the dorsal hippocampus at 24h after SE was analyzed semi-quantitatively in the CA1, CA3 and hilus.
The duration and intensity of electrographic SE was not significantly different across the four groups. In rats treated with NS-398 alone, compared to vehicle-treated rats, neuronal damage was significantly lower compared to vehicle-treated rats in the CA3 (27%) and hilus (27%), but neuroprotection was not detected in the CA1. When NS-398 was administered with diazepam, decreased neuronal damage was further obtained in all areas investigated (CA1: 61%, CA3: 63%, hilus: 60%).
NS-398, when administered 30 min after the onset of SE with a repeat dose at 6h, decreased neuronal damage in the hippocampus. Administration of diazepam with NS-398 potentiates the neuroprotective effect of the COX-2 inhibitor. These neuroprotective effects occurred with no detectable effect on electrographic SE.
癫痫持续状态（SE）期间的癫痫发作会导致神经元死亡并诱导环氧化酶-2（COX-2）。使用毛果芸香碱诱导的SE来确定单独使用NS-398或与地西泮联合使用时，COX-2抑制是否会减少SE的持续时间和/或强度，和/或减少大鼠海马体中的神经元损伤。
将脑电图（EEG）电极植入雄性Sprague-Dawley大鼠体内。用锂-毛果芸香碱诱导SE，并进行24小时的连续EEG和视频监测。大鼠分为四组（每组n = 8 - 14只大鼠），在首次出现运动性癫痫发作后30分钟接受NS-398、地西泮、NS-398和地西泮或赋形剂。6小时后，在NS-398组和NS-398 +地西泮组中重复注射NS-398。分析SE的持续时间（持续棘波）和γ波段的EEG功率。在SE后24小时对背侧海马体进行FluoroJade B染色，并在CA₁、CA₃和齿状回进行半定量分析。
四组之间的脑电图SE的持续时间和强度没有显著差异。与赋形剂处理的大鼠相比，单独用NS-398处理的大鼠中CA₃（27%）和齿状回（27%）的神经元损伤明显低于赋形剂处理的大鼠，但在CA₁中未检测到神经保护作用。当NS-398与地西泮联合使用时，在所有研究区域（CA₁：61%，CA₃：63%，齿状回：60%）中神经元损伤进一步减少。
在SE发作后30分钟给予NS-398并在6小时重复给药，可减少海马体中的神经元损伤。地西泮与NS-398联合使用可增强COX-2抑制剂的神经保护作用。这些神经保护作用在对脑电图SE无明显影响的情况下发生。
