We have previously shown that estradiol (E(2)) can initially increase and then decrease kindle seizure parameters in amygdala kindled male rats. This study focuses on the effects of estradiol benzoate (EB) on afterdischarge (AD) threshold and electrical kindling acquisition in intact male rats. After implantation of tripolar and monopolar electrodes in amygdala and dura surface respectively, effects of EB on AD threshold and electrical kindling acquisition were investigated by daily injection of EB (microg/kg) or sesame oil (EB solvent) in different groups of male rats. AD threshold was reduced significantly 0.25 h post EB treatment and reached to the lowest value after 24 h and remained almost constant at low values. Also, the number of trials for stage 5 (S(5)) and cumulative seconds of AD to complete kindling decreased significantly, when compared to rats without EB treatment. These results support a marked influence of E(2) on seizure process and convulsive pattern in the brain of male rats. Base on the previous reports about female rats and our findings, these E(2) effects are probably not sex dependent.
"The stimulatory and epileptogenic properties of estrogens and their role in the catamenial epilepsy are well established elsewhere (1, 12, 15). Also,rapid stimulatory effects of estradiol (E2) on kindled seizure parameters have been demonstrated previously in male rats ((14, 19, 20, 21). Although, the mechanisms of these diverse effects are not clear, the amplifying effect of E2 on excitatory amino acid activity may play an important role in these complex behaviours. "
[Show abstract][Hide abstract] ABSTRACT: Although the epileptogenic properties of estrogens have been widely demonstrated in several models and species, the mechanism(s) by which estrogens can acutely change seizure parameters including after discharge and seizure durationremains to be determined. In the present study, we examined the role of NMDA (N-methyl-D-aspartate), non-NMDA andestrogen receptors in estradiol benzoate(EB) effects on kindled seizure parameters.
Different groups of fully kindled male rats received either EB (30 μg /Kg); EB plus MK801 (2 mg/Kg, as NMDA antagonist); DNQX (7.5 mg/Kg);tamoxifen (TAM, 0.1 mg/Kg, as non- NMDA antagonist) or intra-amygdala injection of anisomycine (30 mmol/mL, a protein synthesis inhibitor). Kindled seizure parameters including after discharge duration (ADD) and stage 5 duration(S5D) were determined at 0.25 and 3 h post sesame oil (EB solvent) or EB treatment.
While pretreatment with either MK801 or DNQX could block the ADD prolongation induced by EB at 0.25 h, they had no effect on S5D prolongation at 3 h. Moreover, application of anisomycine or TAM had no effect on estradiol induced ADD and S5D prolongation. These results indicate that both NMDA and non-NMDA receptors could be involved in EB induced ADD prolongation. The observed short termnon-estrogenic receptor or protein synthesis dependent effects of EB may provide a non-genomic mechanism for the stimulatory effects of the steroid on seizure activity.
Iranian journal of pharmaceutical research (IJPR) 03/2014; 13(3):987-993. · 1.07 Impact Factor
"Acute administration of estradiol enhances the frequency and severity of PTZ-induced seizures (Reddy, 2004b), an effect consistent with its activity in several experimental models of partial and limbic seizures (Nicoletti et al., 1985; Hom and Buterbaugh, 1986). The proconvulsant-like activity of estradiol is most consistently demonstrated after chronic treatment in male rodents (Pericic et al., 1996; Saberi and Pourgholami, 2003). Further, studies in slices supported the idea that estrogen facilitates hippocampus excitability (Wong and Moss, 1994; Tauboll et al., 1991; Joels, 1997, see review Scharfman and MacLusky, 2006). "
[Show abstract][Hide abstract] ABSTRACT: Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Generally, a twofold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy. Based on this criteria, recent clinical studies indicate that catamenial epilepsy affects 31-60% of the women with epilepsy. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. However, there is no specific drug available today for catamenial epilepsy, which has not been successfully treated with conventional antiepileptic drugs. Elucidation of the pathophysiology of catamenial epilepsy is a prerequisite to develop specific targeted approaches for treatment or prevention of the disorder. Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy. There is emerging evidence that endogenous neurosteroids with anticonvulsant or proconvulsant effects could play a critical role in catamenial epilepsy. It is thought that perimenstrual catamenial epilepsy is associated with the withdrawal of anticonvulsant neurosteroids. Progesterone and other hormonal agents have been shown in limited trials to be moderately effective in catamenial epilepsy, but may cause endocrine side effects. Synthetic neurosteroids, which enhance the tonic GABA-A receptor function, might provide an effective approach for the catamenial epilepsy therapy without producing hormonal side effects.
Epilepsy research 05/2009; 85(1):1-30. DOI:10.1016/j.eplepsyres.2009.02.017 · 2.02 Impact Factor
"Acute administration of 17β-estradiol enhances the frequency and severity of PTZ-induced seizures (Reddy, 2004c), an effect consistent with its activity in several experimental models of partial and limbic seizures (Nicoletti et al., 1985; Hom and Buterbaugh, 1986). The proconvulsant-like activity of estradiol is most consistently demonstrated after chronic treatment (Pericic et al., 1996; Saberi and Pourgholami, 2003). However, 17β-estradiol has rapid effects on increasing field potential amplitudes in hippocampus slices (Wong and Moss, 1991; Tauboll et al., 1994; Joels, 1997), and thus could produce proconvulsant effects in animal models. "
[Show abstract][Hide abstract] ABSTRACT: Steroid hormones play a key role in the pathophysiology of several brain disorders. Testosterone modulates neuronal excitability, but the underlying mechanisms are obscure. There is emerging evidence that testosterone-derived "androgenic neurosteroids", 3alpha-androstanediol and 17beta-estradiol, mediate the testosterone effects on neural excitability and seizure susceptibility. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17beta-estradiol. Reduction of testosterone by 5alpha-reductase generates 5alpha-dihydrotestosterone, which is then converted to 3alpha-androstanediol, a powerful GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Although the 3alpha-androstanediol is an emerging neurosteroid in the brain, there is no specific and sensitive assay for determination of 3alpha-androstanediol in biological samples. This article describes the development and validation of mass spectrometric assay of 3alpha-androstanediol, and the molecular mechanisms underlying the testosterone modulation of seizure susceptibility. A liquid chromatography-tandem mass spectrometry assay to measure 3alpha-androstanediol is validated with excellent linearity, specificity, sensitivity, and reproducibility. Testosterone modulation of seizure susceptibility is demonstrated to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. The proconvulsant effect of testosterone is associated with increases in plasma 17beta-estradiol concentrations. The 5alpha-reduced metabolites of testosterone, 5alpha-dihydrotestosterone and 3alpha-androstanediol, had powerful anticonvulsant activity. Overall, the testosterone-derived neurosteroids 3alpha-androstanediol and 17beta-estradiol could contribute to the net cellular actions of testosterone in the brain. Because 3alpha-androstanediol is a potent positive allosteric modulator of GABA(A) receptors, it could serve as an endogenous neuromodulator of neuronal excitability in men. The 3alpha-androstanediol assay is an important tool in this area because of the growing interest in the potential to use adjuvant aromatase inhibitor therapy to improve treatment of epilepsy.
Neurochemistry International 03/2008; 52(4-5):541-53. DOI:10.1016/j.neuint.2007.05.019 · 3.09 Impact Factor
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