Lakhanpal Dinesh, Kaur Gurcharan
Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
Cell Mol Neurobiol. 2007 Dec;27(8):1069-83. doi: 10.1007/s10571-007-9201-x. Epub 2007 Sep 7.
SUMMARY OF THE AIMS: Women with epilepsy using antiepileptic drug valproic acid (VPA) often suffer from reproductive endocrine disorders, menstrual disorders and polycystic ovaries. Valproic acid exerts anticonvulsive effects via gamma amino butyric acid (GABA) neurotransmitter system, which also acts as a neurochemical regulator of gonadotropin-releasing hormone (GnRH) neurons and suggests possibility of valproic acid mediated interruption in gonadotropin releasing hormone pulse generator in hypothalamus. The aim of this study was to investigate the effects of valproic acid treatment on the expression of gonadotropin releasing hormone, gamma amino butyric acid and polysialylated form of neural cell adhesion molecule (PSA-NCAM) a marker of neuronal plasticity in the median preoptic area (mPOA) and median eminence-arcuate (ME-ARC) region having GnRH neuron cell bodies and axon terminals, respectively.
Three-month-old virgin Wistar strain female rats received VPA (i.p.) at a dose of 300 mg/kg once a day for 12 weeks; control group received an equivalent volume of vehicle. GnRH, GABA and PSA-NCAM expressions were studied by immunohistofluorescence technique from mPOA and ME-ARC region of hypothalamus. Ovarian histology was also studied using Mayer's Haematoxylin-Eosin staining method.
GnRH and PSA-NCAM staining was much higher in mPOA and ME-ARC region from vehicle treated control proestrous rats, whereas VPA treatment significantly enhanced GABA expression, and reduced both GnRH and PSA-NCAM expression. Mayer's Haematoxylin-Eosin staining of mid-ovarian sections revealed significantly higher number of ovarian follicular cysts in VPA treated rats.
Our findings of alterations in GnRH and GABA expression and GnRH neuronal plasticity marker PSA-NCAM as well as changes in ovarian histology suggest that treatment with VPA disrupts hypothalamo-hypophyseal-gonadal axis (HPG) at the level of GnRH pulse generator in hypothalamus.
研究目的总结：使用抗癫痫药物丙戊酸（VPA）的癫痫女性常患有生殖内分泌紊乱、月经失调和多囊卵巢。丙戊酸通过γ-氨基丁酸（GABA）神经递质系统发挥抗惊厥作用，该系统也是促性腺激素释放激素（GnRH）神经元的神经化学调节剂，提示丙戊酸可能介导下丘脑促性腺激素释放激素脉冲发生器的中断。本研究的目的是调查丙戊酸治疗对促性腺激素释放激素、γ-氨基丁酸和神经细胞黏附分子多唾液酸化形式（PSA-NCAM，神经元可塑性标志物）表达的影响，这些标志物分别位于视前正中区（mPOA）和正中隆起-弓状核（ME-ARC）区域，其中前者含有GnRH神经元细胞体，后者含有GnRH轴突终末。
3月龄未交配的Wistar品系雌性大鼠每天腹腔注射一次300 mg/kg的VPA，持续12周；对照组注射等量的溶剂。通过免疫荧光技术研究下丘脑mPOA和ME-ARC区域的GnRH、GABA和PSA-NCAM表达。还使用梅耶苏木精-伊红染色法研究卵巢组织学。
在接受溶剂处理的对照动情前期大鼠的mPOA和ME-ARC区域，GnRH和PSA-NCAM染色要高得多，而VPA治疗显著增强了GABA表达，并降低了GnRH和PSA-NCAM表达。卵巢中部切片的梅耶苏木精-伊红染色显示，VPA处理的大鼠卵巢滤泡囊肿数量明显更多。
我们关于GnRH和GABA表达变化、GnRH神经元可塑性标志物PSA-NCAM以及卵巢组织学变化的研究结果表明，VPA治疗在下丘脑GnRH脉冲发生器水平破坏了下丘脑-垂体-性腺轴（HPG）。
