Tran V, Hatalski C G, Yan X X, Baram T Z
Department of Pediatrics, University of California at Irvine, 92697-4475, USA.
Epilepsia. 1999 Sep;40(9):1190-7. doi: 10.1111/j.1528-1157.1999.tb00847.x.
The gamma-aminobutyric acid (GABA) degradation blocker gamma-vinyl-GABA (VGB) is used clinically to treat seizures in both adult and immature individuals. The mechanism by which VGB controls developmental seizures is not fully understood. Specifically, whether the anticonvulsant properties of VGB arise only from its elevation of brain GABA levels and the resulting activation of GABA receptors, or also from associated mechanisms, remains unresolved. Corticotropin-releasing hormone (CRH), a neuropeptide present in many brain regions involved in developmental seizures, is a known convulsant in the immature brain and has been implicated in some developmental seizures. In certain brain regions, it has been suggested that CRH synthesis and release may be regulated by GABA. Therefore we tested the hypothesis that VGB decreases CRH gene expression in the immature rat brain, consistent with the notion that VGB may decrease seizures also by reducing the levels of the convulsant molecule, CRH.
VGB was administered to immature, 9-day-old rats in clinically relevant doses, whereas littermate controls received vehicle.
In situ hybridization histochemistry demonstrated a downregulation of CRH mRNA levels in the hypothalamic paraventricular nucleus but not in other limbic regions of VGB-treated pups compared with controls. In addition, VGB-treated pups had increased CRH peptide levels in the anterior hypothalamus, as shown by radioimmunoassay.
These findings are consistent with a reduction of both CRH gene expression and secretion in the hypothalamus, but do not support an indirect anticonvulsant mechanism of VGB via downregulation of CRH levels in limbic structures. However, the data support a region-specific regulation of CRH gene expression by GABA.
γ-氨基丁酸（GABA）降解阻滞剂γ-乙烯基-GABA（VGB）在临床上用于治疗成人和未成熟个体的癫痫发作。VGB控制发育性癫痫发作的机制尚未完全明确。具体而言，VGB的抗惊厥特性是仅源于其提高脑内GABA水平并由此激活GABA受体，还是也源于相关机制，仍未得到解决。促肾上腺皮质激素释放激素（CRH）是一种存在于许多与发育性癫痫发作相关脑区的神经肽，在未成熟脑内是一种已知的惊厥剂，并且与某些发育性癫痫发作有关。在某些脑区，有人提出CRH的合成和释放可能受GABA调节。因此，我们检验了这样一个假说，即VGB可降低未成熟大鼠脑内CRH基因表达，这与VGB也可能通过降低惊厥分子CRH的水平来减少癫痫发作的观点相一致。
以临床相关剂量给9日龄未成熟大鼠给予VGB，而其同窝对照给予赋形剂。
与对照组相比，原位杂交组织化学显示，VGB处理幼鼠的下丘脑室旁核中CRH mRNA水平下调，但在其他边缘脑区未下调。此外，放射免疫测定显示，VGB处理的幼鼠下丘脑前部的CRH肽水平升高。
这些发现与下丘脑CRH基因表达和分泌的减少一致，但不支持VGB通过下调边缘结构中CRH水平的间接抗惊厥机制。然而，这些数据支持GABA对CRH基因表达的区域特异性调节。
