Smyth Matthew D, Barbaro Nicholas M, Baraban Scott C
Department of Neurological Surgery, Epilepsy Research Laboratory, University of California at San Francisco, 94143-0112, USA.
Epilepsy Res. 2002 Aug;50(3):251-64. doi: 10.1016/s0920-1211(02)00051-7.
Seizure activity associated with cortical dysplasia (CD) is often resistant to standard pharmacologic treatments. Although several animal models exhibit CD, virtually nothing is known about antiepileptic drug (AED) responses in these animals. Here we have used rats exposed to methylazoxymethanol acetate (MAM) in utero, an animal model featuring nodular heterotopia, to investigate the effects of AEDs in the dysplastic brain. 4-aminopyridine (100 microM), a K(+) channel blocker, was used to induce interictal epileptiform bursting in acute hippocampal slices from MAM-exposed and age-matched vehicle-injected control animals. Extracellular field recordings were used to monitor seizure activity in vitro. Five commonly used AEDs were tested: phenobarbital, 25-400 microM; carbamazepine, 25-200 microM; valproate (VPA), 0.19-4 mM; ethosuximide (ESM), 0.5-8 mM; and lamotrigine (LTG), 49-390 microM. 4-AP-induced bursting occurred with shorter latencies in slices from MAM-exposed rats in comparison with slices from controls, confirming the intrinsic hyperexcitability of dysplastic tissue. Each AED tested demonstrated significant burst suppression in control slices, but interictal epileptiform bursting in MAM-exposed slices was resistant to these treatments. Even at the highest concentrations, VPA, ESM and LTG had no effect on burst amplitude in slices from MAM-exposed rats. Pharmaco-resistance was further tested by measuring seizure latencies in awake, freely-moving rats after kainate administration (15 mg/kg, i.p.) with and without pre-treatment with VPA (400 mg/kg i.p.). Pre-treatment with VPA prolonged seizure latency in control rats, but had no effect in MAM-exposed animals. These results suggest MAM-exposed rats exhibit a dramatically reduced sensitivity to commonly prescribed AEDs.
与皮质发育异常（CD）相关的癫痫发作活动通常对标准药物治疗有抵抗性。尽管有几种动物模型表现出CD，但对于这些动物对抗癫痫药物（AED）的反应几乎一无所知。在此，我们使用了在子宫内暴露于乙酸甲基氧化偶氮甲醇（MAM）的大鼠，这是一种具有结节性异位的动物模型，来研究AEDs对发育异常脑的影响。4-氨基吡啶（100微摩尔），一种钾（K+）通道阻滞剂，用于诱导来自暴露于MAM的大鼠和年龄匹配的注射溶剂对照动物的急性海马切片中的发作间期癫痫样爆发。细胞外场记录用于监测体外的癫痫发作活动。测试了五种常用的AEDs：苯巴比妥，25 - 400微摩尔；卡马西平，25 - 200微摩尔；丙戊酸（VPA），0.19 - 4毫摩尔；乙琥胺（ESM），0.5 - 8毫摩尔；以及拉莫三嗪（LTG），49 - 390微摩尔。与对照切片相比，4-AP诱导的爆发在来自暴露于MAM的大鼠的切片中潜伏期更短，证实了发育异常组织的内在兴奋性过高。测试的每种AED在对照切片中均显示出显著的爆发抑制，但暴露于MAM的切片中的发作间期癫痫样爆发对这些治疗有抵抗性。即使在最高浓度下，VPA、ESM和LTG对来自暴露于MAM的大鼠的切片中的爆发幅度也没有影响。通过测量在给予海藻酸（15毫克/千克，腹腔注射）后清醒、自由活动的大鼠的癫痫发作潜伏期，在有和没有VPA预处理（400毫克/千克腹腔注射）的情况下，进一步测试了药物抵抗性。VPA预处理延长了对照大鼠的癫痫发作潜伏期，但对暴露于MAM的动物没有影响。这些结果表明，暴露于MAM的大鼠对常用的AEDs表现出显著降低的敏感性。
