Löscher W, Ebert U, Lehmann H, Rosenthal C, Nikkhah G
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
J Neurosci Res. 1998 Jan 15;51(2):196-209. doi: 10.1002/(SICI)1097-4547(19980115)51:2<196::AID-JNR8>3.0.CO;2-8.
Compared with studies on models of neurodegenerative diseases, considerably less work has been performed with neural grafts in experimental epilepsy. The potential value of this approach, however, is already shown by evidence that noradrenergic grafts implanted bilaterally into the hippocampus or amygdala-piriform cortex can suppress seizure development in the kindling model of temporal lobe epilepsy. We previously showed that amygdala kindling results in a significant decrease of GABA and its synthesizing enzyme glutamate decarboxylase in substantia nigra (SN), i.e., a region thought to be critically involved in seizure propagation in various models of epilepsy. Thus, transplantation of fetal GABAergic neurons into SN might be an effective means of permanently blocking seizure generalization in kindling epilepsy and probably also other types of epilepsy. To test this hypothesis, three groups of female Wistar rats (n = 10 per group) were kindled by electrical stimulation via a bipolar electrode in the basolateral amygdala. After all rats were fully kindled, one group was implanted with GABA-rich cells prepared from the striatal eminence of Wistar rat fetuses at embryonic day 14. The striatal neurons were bilaterally microinjected at various sites over the anterior-posterior axis of the SN, aimed at the pars reticulata. The second group received microinjections of spinal cord cell preparations, whereas the third group received microinjections of cell-free medium only. In all rats, the threshold for focal discharges (afterdischarge threshold [ADT]) as well as afterdischarge duration and severity and duration of seizures occurring at ADT current were determined once weekly before and after transplantation. Eleven to 12 weeks following transplantation, the rats were killed, and location and integration of grafts were examined by immunohistological methods. Rats with GABAergic grafts in SN exhibited a significant increase in ADT and marked reduction in seizure severity compared with pretransplantation values, whereas no such alteration was seen in the other groups. However, the seizure-suppressing effect of GABAergic grafts was not permanent but slowly disappeared over the weeks after transplantation. Although the data indicate that intranigral transplantation of GABA-producing cells is no effective means of inducing long-lasting anticonvulsant effects in experimental epilepsy, this approach may be an initial step to develop more efficient strategies for seizure suppression.
与神经退行性疾病模型的研究相比，在实验性癫痫中使用神经移植的研究要少得多。然而，这种方法的潜在价值已经通过以下证据得以体现：双侧植入海马体或杏仁核 - 梨状皮质的去甲肾上腺素能移植体可以抑制颞叶癫痫点燃模型中的癫痫发作发展。我们之前表明，杏仁核点燃会导致黑质（SN）中γ-氨基丁酸（GABA）及其合成酶谷氨酸脱羧酶显著减少，也就是说，在各种癫痫模型中，该区域被认为在癫痫传播中起关键作用。因此，将胎儿GABA能神经元移植到黑质可能是永久阻断点燃性癫痫以及可能其他类型癫痫中癫痫发作泛化的有效手段。为了验证这一假设，将三组雌性Wistar大鼠（每组n = 10）通过双极电极在基底外侧杏仁核进行电刺激点燃。所有大鼠完全点燃后，一组植入从胚胎第14天的Wistar大鼠胎儿纹状体隆起制备的富含GABA的细胞。将纹状体神经元双侧微量注射到黑质前后轴的不同部位，目标是黑质网状部。第二组接受脊髓细胞制剂的微量注射，而第三组仅接受无细胞培养基的微量注射。在所有大鼠中，在移植前后每周测定一次局灶性放电阈值（后放电阈值[ADT]）以及在ADT电流下发生的后放电持续时间、癫痫发作严重程度和持续时间。移植11至12周后，处死大鼠，并通过免疫组织学方法检查移植体的位置和整合情况。与移植前的值相比，黑质中有GABA能移植体的大鼠ADT显著增加，癫痫发作严重程度明显降低，而其他组未见这种改变。然而，GABA能移植体的癫痫抑制作用不是永久性的，而是在移植后的几周内逐渐消失。尽管数据表明在实验性癫痫中，向黑质内移植产生GABA的细胞不是诱导长期抗惊厥作用的有效手段，但这种方法可能是开发更有效癫痫抑制策略的第一步。
