Valproate and neuroendocrine changes in relation to women treated for epilepsy and bipolar disorder: a review.

Yale University School of Medicine, New Haven, CT 06510, USA.
Current Medicinal Chemistry (Impact Factor: 3.72). 02/2007; 14(26):2799-812. DOI: 10.2174/092986707782360088
Source: PubMed

ABSTRACT Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Valproic acid (VPA), a short-chain fatty acid that is a histone deacetylase (HDAC) inhibitor, is known to suppress adipogenesis. In this study, we identified the molecular mechanism of VPA-mediated suppression of adipogenesis in adipocytes. VPA suppressed the accumulation of intracellular triglycerides. The expression levels of peroxisome proliferator-activated receptor γ and CCAAT/enhancer binding protein α, which are key regulators of adipogenesis, as well as the expression of stearoyl-CoA desaturase, were decreased by the treatment with VPA. Moreover, glycerol release was decreased in the VPA-treated cells; even though the transcription levels of adipose triglyceride lipase, hormone sensitive lipase, and monoacylglycerol lipase, all of which are involved in lipolysis, were elevated by the treatment with VPA. Noteworthily, the expression level of fatty acid synthase (FAS) was significantly suppressed when the cells were cultured in medium containing VPA. Furthermore, VPA-mediated suppression of the accumulation of the intracellular triglycerides was prevented by the treatment with palmitic acid, a major product of FAS. The results of promoter-luciferase and chromatin immunoprecipitation assays demonstrated that upstream stimulating factor 1 (USF1) bound to the E-box of the promoter region of the FAS gene. In addition, the expression of USF1 was decreased by the treatment with VPA. siRNA-mediated knockdown of the expression of the USF1 gene repressed adipogenesis along with the decreased expression of the FAS gene. The overexpression of USF1 enhanced both adipogenesis and the expression of FAS in VPA-treated cells. These results indicate that VPA suppressed adipogenesis through the down-regulation of USF1-activated fatty acid synthesis in adipocytes.
    Biochemical Journal 02/2014; · 4.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review discusses the diagnosis and detection of bipolar disorder in the primary care population with recent changes introduced by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and the pharmacotherapy and psychosocial management of this psychiatric condition.
    Medical Clinics of North America 09/2014; 98(5):1025–1048. · 2.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The effects of hyperglycemia on the pharmacokinetics of valproic acid (VPA) were examined by time-concentration profiles of plasma VPA accompanied with blood glucose (BG) changing. In addition, time-concentration profiles of plasma free fatty acids (FFAs) were also obtained to examine the interaction between VPA and FFAs in vivo. For the experiments in vivo, normal rats, given multiple doses of maltose orally, and diabetic rats, which were made to maintain hyperglycemia, were used. Plasma VPA and FFA were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) systems based on the reduction of quinone for the selective determination of acids, respectively. BG was determined by pocket-size glucose meter. The maximum plasma concentrations (Cmax) of VPA in normal rats given multiple doses of maltose orally and in diabetic rats were remarkably decreased in comparison with those in the control rats. From the present study, it was shown that the metabolism of plasma VPA is accelerated under hyperglycemia. Moreover, we also found that VPA was preferentially metabolized in comparison with the plasma FFA in vivo.
    Journal of pharmaceutical and biomedical analysis 04/2014; 97C:47-53. · 2.45 Impact Factor