Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats
Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats
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DOI：
10.3171/jns.2001.94.2.0270
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发表时间：
2001-02-01
影响因子：
4.1
通讯作者：
Lee, KS
中科院分区：
文献类型：
--
作者：
Chen, ZF;Kamiryo, T;Lee, KS
对象。难治性癫痫的管理仍然是一个挑战，尽管其手术和非手术治疗的进展。因此，确定低风险、低成本的治疗策略是基础和临床研究的一个重要目标。采用已建立的大鼠慢性复发性自发性边缘癫痫模型，研究了坏死诱导和亚坏死水平单剂量局灶电离束辐射对癫痫发作活动的影响。对大鼠海马进行一次90分钟的重复电刺激（诱导刺激），引起一次癫痫持续状态，随后是2至4周的无癫痫期。随后发生自发性复发性癫痫发作，并持续监测时间（2-10个月）。同时采用计算机脑电图和视频记录对动物进行监测。在确定自发性复发性癫痫发作后，在为小动物定制的立体定向装置的辅助下，用Leksell伽玛刀对以海马腹侧为中心的双侧进行辐射。使用4毫米准直器给予10、20或40戈瑞的中心剂量。对照动物受到同样的诱发癫痫的刺激，但接受假治疗而不是伽马辐射。在第二个实验中，作者检测了伽马辐射对海马神经元呈现癫痫样放电倾向的影响。如前所述，幼稚动物接受单次40戈瑞剂量的辐射。海马体切片是在辐射后1至178天内死亡的动物身上制备的。研究了对照和辐照大鼠脑片对青霉素诱导的癫痫样尖刺的敏感性。在第一个实验中，单次剂量20或40 Gy（但不是10 Gy）大大减少，在某些情况下消除了行为和电图识别的癫痫发作。在治疗后长达10个月的随访期间，观察到自发性癫痫发作的频率和持续时间显著减少。靶区组织学检查未见坏死迹象。这些发现表明，在坏死剂量下的单剂量局灶电离束照射可减少或消除颞叶癫痫大鼠模型的重复性自发发作。在第二个实验中，突触驱动的神经元放电在海马神经元中受到40 gy剂量的影响是完整的。然而，与未受辐射的对照大鼠相比，接受40 gy剂量的动物脑切片对青霉素诱导的癫痫样活动的易感性降低。本研究结果为应用坏死下伽玛照射治疗癫痫提供了合理的支持。这些发现还提供证据表明，海马神经元癫痫阈值的功能性增加有助于坏死性γ照射的抗惊厥作用。
Object. The management of intractable epilepsy remains a challenge, despite advances in its surgical and nonsurgical treatment. The identification of low-risk, low-cost therapeutic strategies that lead to improved outcome is therefore an important ongoing goal of basic and clinical research. Single-dose focal ionizing beam radiation delivered at necrosis-inducing and subnecrotic levels was investigated for its effects on seizure activity by using an established model of chronic recurrent spontaneous limbic seizures in rats.Methods. A single 90-minute period of repetitive electrical stimulation (inducing stimulus) of the hippocampus in rats elicited a single episode of status epilepticus, followed by a 2- to 4-week seizure-free period. Spontaneous recurrent seizures developed subsequently and persisted for the duration of monitoring (2-10 months). Simultaneous computerized electroencephalography and video recording were used to monitor the animals. After the establishment of spontaneous recurrent seizures, bilateral radiation centered in the ventral hippocampal formation was administered with the Leksell gamma knife, aided by a stereotactic device custom made for small animals. A center dose of 10, 20, or 40 Gy was administered using a 4-mm collimator. Control animals were subjected to the same seizure-inducing stimulus but underwent a sham treatment instead of gamma irradiation.In a second experiment, the authors examined the effects of gamma irradiation on the proclivity of hippocampal neurons to display epileptiform discharges. Naive animals were irradiated with a single 40-Gy dose, as already described. Slices of the hippocampus were prepared from animals killed between 1 and 178 days postirradiation. Sensitivity to penicillin-induced epileptiform spiking was examined in vitro in slices prepared from control and irradiated rat brains.Conclusions. In the first experiment, single doses of 20 or 40 Cy (but not 10 Gy) reduced substantially, and in some cases eliminated, behaviorally and electrographically recognized seizures. Significant reductions in both the frequency and duration of spontaneous seizures were observed during a follow-up period of up to 10 months postradiation. Histological examination of the targeted region did not reveal signs of necrosis. These findings indicate that single-dose focal ionizing beam irradiation at subnecrotic dosages reduces or eliminates repetitive spontaneous seizures in a rat model of temporal lobe epilepsy. In the second experiment, synaptically driven neuronal firing was shown to be intact in hippocampal neurons subjected to 40-Gy doses. However, the susceptibility to penicillin-induced epileptiform activity was reduced in the brain slices of animals receiving 40-Gy doses, compared with those from control rats that were not irradiated. The results provide rational support for the utility of subnecrotic gamma irradiation as a therapeutic strategy for treating epilepsy. These findings also provide evidence that a functional increase in the seizure threshold of hippocampal neurons contributes to the anticonvulsant influence of subnecrotic gamma irradiation.