Neural transplantation of GABA-producing cells into key structures within seizure-suppressing circuits holds promise for medication-resistant epilepsy patients not eligible for resection of the epileptic focus. The substantia nigra pars reticulata (SNr), a basal ganglia output structure, is well known to modulate different seizure types. A recent microinjection study by our group indicated that the subthalamic nucleus (STN), which critically regulates nigral activity, might be a more promising target for focal therapy in epilepsies than the SNr. As a proof of principle, we therefore assessed the anticonvulsant efficacy of bilateral and unilateral allografting of GABA-producing cell lines into the STN using the timed intravenous pentylenetetrazole seizure threshold test, which allows repeated seizure threshold determinations in individual rats. We observed (a) that grafted cells survived up to the end of the experiments, (b) that anticonvulsant effects can be induced by bilateral transplantation into the STN using immortalized GABAergic cells derived from the rat embryonic striatum and cells additionally transfected to obtain higher GABA synthesis than the parent cell line, and (c) that anticonvulsant effects were observed even after unilateral transplantation into the STN. Neither grafting of control cells nor transplantation outside the STN induced anticonvulsant effects, emphasizing the site and cell specificity of the observed anticonvulsant effects. To our knowledge, the present study is the first showing anticonvulsant effects by grafting of GABA-producing cells into the STN. The STN can be considered a highly promising target region for modulation of seizure circuits and, moreover, has the advantage of being clinically established for functional neurosurgery.

译文

:GABA产生细胞的神经移植到癫痫抑制回路内的关键结构中,对于那些不适合切除癫痫病灶的耐药性癫痫患者有希望。黑质网状体(SNr)是一种基底神经节输出结构,众所周知可以调节不同的癫痫发作类型。我们小组最近进行的显微注射研究表明,与SNr相比,关键调节黑质活动的丘脑下核(STN)可能是癫痫病灶治疗中更有希望的靶标。作为原理的证明,因此,我们使用定时静脉内戊烯四唑癫痫发作阈值试验评估了将GABA产生的细胞系双边和单侧同种异体移植到STN中的抗惊厥功效,该试验可重复测定单个大鼠的癫痫发作阈值。我们观察到(a)移植的细胞可以存活到实验结束,(b)使用永生化的GABA鼠源性纹状体,可以将双侧移植到STN中诱导抗惊厥作用,这种细胞可以通过转染以获得更高的GABA来获得。 (c)即使单方面移植到STN中也观察到抗惊厥作用。既不移植对照细胞也不在STN外部移植诱导抗惊厥作用,强调观察到的抗惊厥作用的部位和细胞特异性。据我们所知,本研究是第一个通过将产生GABA的细胞移植到STN中来显示抗惊厥作用的研究。 STN可以被认为是调节癫痫发作电路的高度有希望的目标区域,而且具有在临床上为功能性神经外科手术建立的优势。

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