Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, India.
Acta Neurol Belg. 2011 Jun;111(2):121-9.
Valproic acid (VPA) has been used for > 30 years in the treatment of epilepsy and is now one of the most frequently prescribed anti-epileptic drugs (AEDs) worldwide. Its chronic use has been associated with hyperandrogenism and polycystic ovaries in women with epilepsy and thus suggests change in normal levels of estrogens--the gonadal steroids in females. We have tested the hypothesis whether AEDs that exert anticonvulsive effects via key molecules of the gamma amino butyric acid (GABAergic) system, have inhibitory effects on the hypothalamo-hypophyseal-gonadal (HPG) axis at the level of hypothalamic gonadotropin releasing hormone (GnRH) synthesis and/or release and thereby affect reproductive health. Three-month old female Wistar rats were given VPA (i.p.) at a dose of 300 mg/Kg once a day for 12 weeks; the control group received an equivalent volume of vehicle. Glutamic acid decarboxylase (GAD), glial fibrillary acidic protein (GFAP) and their mRNA expression in the median eminence arcuate region (ME-ARC) of the hypothalamus were upregulated in the VPA treated group. By contrast, polysialyltransferase (PST) mRNA which is the enzyme responsible for the polysialylation of neural cell adhesion molecule (NCAM), a plasticity marker, was found to be downregulated. These results support our hypothesis that VPA disrupts normal neuronal-glial plasticity in the hypothalamus and can thereby cause reproductive neuroendocrine disorders in female patients treated for epilepsy, bipolar disorder or migraine.
丙戊酸（VPA）在治疗癫痫方面已使用超过 30 年，现已成为全球最常开的抗癫痫药物（AEDs）之一。其长期使用与癫痫女性的高雄激素血症和多囊卵巢有关，这表明雌激素——女性的性腺类固醇——的正常水平发生了变化。我们已经验证了这样一个假设，即通过γ-氨基丁酸（GABAergic）系统的关键分子发挥抗惊厥作用的 AEDs 是否会在 GnRH 合成和/或释放的下丘脑水平上对下丘脑-垂体-性腺（HPG）轴产生抑制作用，从而影响生殖健康。3 个月大的雌性 Wistar 大鼠每天接受 300mg/Kg 的 VPA（ip）一次，共 12 周；对照组接受等量的载体。谷氨酸脱羧酶（GAD）、胶质纤维酸性蛋白（GFAP）及其在下丘脑弓状核区域（ME-ARC）的 mRNA 表达在 VPA 处理组中上调。相比之下，多唾液酸转移酶（PST）mRNA——负责神经细胞粘附分子（NCAM）多聚唾液酸化的酶，被发现下调。这些结果支持我们的假设，即 VPA 破坏了下丘脑正常的神经元-神经胶质可塑性，并由此导致接受癫痫、双相情感障碍或偏头痛治疗的女性患者出现生殖神经内分泌紊乱。
