Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells Into the Subthalamic Nucleus in an Acute Seizure Model
Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells Into the Subthalamic Nucleus in an Acute Seizure Model
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DOI：
10.3727/096368912x658944
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发表时间：
2014-01-01
影响因子：
3.3
通讯作者：
Gernert, Manuela
中科院分区：
文献类型：
--
作者：
Handreck, Annelie;Backofen-Wehrhahn, Bianca;Gernert, Manuela
将GABA产生细胞神经移植到神经抑制回路内的关键结构中，为不适合切除癫痫病灶的耐药性癫痫患者带来了希望。黑质网状部（SNr），基底神经节的输出结构，是众所周知的，以调节不同的癫痫发作类型。我们小组最近的一项显微注射研究表明，丘脑底核（subthalamic nucleus，简称SNR），它对黑质的活性起着关键性的调节作用，可能是一个比SNR更有前途的癫痫局灶性治疗靶点。作为一个原则的证明，我们因此评估了双边和单边同种异体移植GABA生产细胞系的抗惊厥疗效，使用定时静脉戊四唑癫痫发作阈值测试，允许重复癫痫发作阈值测定在个别大鼠。我们观察到：（a）移植的细胞存活至实验结束，（B）使用来自大鼠胚胎纹状体的永生化GABA能细胞和额外转染以获得比亲本细胞系更高的GABA合成的细胞，通过双侧移植到小脑中可以诱导抗惊厥作用，和（c）甚至在单侧移植到小脑中后也观察到抗惊厥作用。无论是移植的控制细胞，也没有移植外诱导的抗惊厥作用，强调的网站和细胞特异性观察到的抗惊厥作用。据我们所知，目前的研究是第一次显示抗惊厥作用的GABA生产细胞移植到小脑。STN可以被认为是调节癫痫发作回路的非常有希望的目标区域，此外，它还具有在临床上建立用于功能神经外科的优势。
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.