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: 2.51). 01/2008; 27(8):1069-83. DOI: 10.1007/s10571-007-9201-x
Source: PubMed


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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    • "However, the mechanism through which VPA may induce weight gain is still unknown. Currently, research studying the effect of VPA on weight gain has focused on various hypotheses, such as dysregulation of the hypothalamic system (Lakhanpal and Kaur, 2007), hyperleptinaemia , and LEP resistance (Gungor et al., 2007; Hamed et al., 2009; Verrotti et al., 2011; Kanemura et al., 2012), but there is no single mechanism that can explain VPA-induced weight gain. "
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    ABSTRACT: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggestes that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of SNPs in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using Sequenom MassArray iPlex platform, and VPA Css was determined by HPLC. After six months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥ 7%). Three SNPs in leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1) and α catalytic subunit of AMPK (PRKAA2) showed significant associations with VPA-induced weight gain (p<0.001, p=0.017 and p=0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101 and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p=0.121). LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 03/2015; 18(7). DOI:10.1093/ijnp/pyv021 · 4.01 Impact Factor
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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 · 2.02 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). "
    Endocrine Toxicology, 3rd edited by J C Eldridge, J T Stevens, 02/2010: pages 210-239; Informa Healthcare., ISBN: 1-4200-9309-6
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