Valproic acid alters GnRH-GABA interactions in cycling female rats

Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
Cellular and Molecular Neurobiology (Impact Factor: 2.2). 01/2008; 27(8):1069-83. DOI: 10.1007/s10571-007-9201-x
Source: PubMed

ABSTRACT 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.

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    • "The mechanism through which VPA may induce a weight gain is matter of discussion. However, various hypotheses have been submitted to explain the effect of VPA on weight increase: dysregulation of the hypothalamic system, effect on adipokine levels, hyperinsulinaemia , IR. Experimental data have demonstrated that VPA can cause dysregulation of the hypothalamic system (Lakhanpal and Kau, 2007). This theory may be explained by the enhancement of GABA transmission within the hypothalamic axis (Biton et al., 2003) and it is supported "
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    ABSTRACT: Treatment of epileptic patients with valproic acid (VPA) may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. VPA-induced weight gain seems to be associated with many metabolic disturbances; the most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance. Patients who gain weight during VPA therapy can develop dyslipidemia and metabolic syndrome that are associated with long-term vascular complications such as hypertension and atherosclerosis. Moreover, an elevation in the levels of uric acid and homocysteine, together with oxidative stress, may contribute to atherosclerotic risk in patients under long-term therapy with VPA. The aim of this review is to discuss the metabolic and endocrine effects of VPA chronic treatment in patients with epilepsy.
    Epilepsy research 09/2013; 107(1-2). DOI:10.1016/j.eplepsyres.2013.08.016 · 2.19 Impact Factor
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    • "At this dose, LH concentrations were also decreased in female rats after blood samples were taken at the conclusion of more extended three-month treatments (Sveberg Røste et al., 2002). Administration was reported to increase GABAimmunoreactive cell bodies in the median eminence-ARC region and to decrease GnRH in the same area, along with a similar decline in the medial preoptic region (Lakhanpal and Kaur, 2007). Published data have also shown that GABA A receptors, in addition to inhibiting GnRH neurons (Han et al., 2004), can depolarize/excite them (Moenter and DeFazio, 2005). "
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    ABSTRACT: Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial. In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically. Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic beta-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects. The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research.
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