Interactive reportSex differences in models of temporal lobe epilepsy: role of testosterone
Introduction
Sex hormones modulate brain function throughout the life span of an organism. During early development they regulate the process of sexual differentiation and are involved in the maturation of many brain structures such as the hypothalamus and the hippocampus [2], [26]. In adulthood, levels of plasma sex steroids may influence the progression of neurological disorders such as Parkinson’s, Alzheimer’s, and epilepsy [10], [30].
The relationship between sex steroids and epilepsy has been reported since the 1950s. These early studies found a correlation between the stage of the menstrual cycle and seizure susceptibility, a phenomenon coined as catamenial epilepsy. An increase in seizure frequency was observed near the time of menstruation, when plasma levels of sex steroids are low [33] and prior to ovulation, coinciding with the pre-ovulatory surge of estrogen [3]. These and other studies suggested that estrogen has an exacerbating effect and progesterone a protective effect on seizure susceptibility [3], [39]. In view of this, progesterone therapy has been used effectively in women with complex partial seizures to diminish the frequency of seizures [19].
Most studies investigating the role of sex steroids in seizure susceptibility have been conducted in females, even though the prevalence of the epileptic syndrome, as well as the risk to manifest a first unprovoked seizure, is higher in men than in women [17]. The etiology for this sex difference has been partially attributed to the higher trauma-related epileptic syndrome in males. However, if only idiopathic seizures are considered, while the sex difference is reduced, men are still more prone to have seizures than women [17]. Men also exhibit more seizure-associated brain damage than women [5].
A reduction in plasma testosterone levels is also observed in many male epileptic patients. Whether this decrease in testosterone is a consequence of seizures or of treatment with anticonvulsive drugs is still controversial. Many antiepileptic drugs such as carbamazepine and phenytoin are known to increase testosterone metabolism [41], [48] and plasma levels of sex-hormone binding globulin [11], [24], [47], [54], decreasing the amount of free testosterone in plasma. Nonetheless, a study in rodents suggests that seizures per se can affect plasma levels of sex steroids [12]. These authors found that electroconvulsive shock decreased plasma testosterone levels whereas kindling of the amygdala had an opposite effect on testosterone levels.
In some patients, the decrease in plasma testosterone is accompanied by an increase in plasma estradiol levels [21], [23], [38]. Treatment of these patients with testolactone, an aromatase inhibitor, decreases the frequency of temporal lobe seizures [21]. These results suggest an additional route by which testosterone may affect seizure susceptibility: via aromatization to estradiol. In agreement, a decrease in the threshold to afterdischarges induced by kindling of the amygdala is observed in gonadectomized male rats treated with estradiol [13].
Sex differences in seizure susceptibility have also been reported in animal models of generalized seizures although recent studies present contradictory data [6], [15], [29], [31], [37], [42], [43], [44], [52], [58]. However very few studies have used animal models of temporal lobe epilepsy. Kainic acid and pilocarpine have been the most widely used chemical models for the induction of temporal lobe seizures. Both models present a similar progression of seizure stereotypic behavior, beginning with limbic automatisms, the production of tonic–clonic seizures and status epilepticus. In addition, both models produce neuronal damage similar to that observed in patients with temporal lobe epilepsy [9], [35], [53], [59]. Accordingly, we tested the hypothesis that sex differences exist in the susceptibility to temporal lobe seizures using the kainic acid and pilocarpine models in rodents. In addition, we investigated if testosterone can alter the susceptibility to kainate-induced seizures, and if kainic acid-induced seizures can alter plasma levels of testosterone.
Section snippets
Materials and methods
Adult male and female Sprague–Dawley rats (9 weeks) were housed in groups of 2–3 of the same sex and provided with water and Purina rat chow ad libitum. Rats were maintained on a 12L:12D photoperiod, with lights on at 06:00 h. All animal procedures were approved by the Institutional Animal Welfare Committee and followed USDA guidelines for the Use and Care of Laboratory Animals.
Behavioral sex differences
Sex differences were observed in the latency and in the frequency to kainate-induced full limbic seizures (Table 1). Although females have a shorter latency to mild and full limbic convulsions, males exhibit a higher frequency of full limbic convulsions. Thus, seizure onset is slower but seizures are stronger and more frequent in males than in females. Gender differences in pilocarpine-induced seizures were also observed (Table 2). More males exhibited full limbic convulsions and status
Sex differences
Results from this study indicate that the male is more susceptible to the convulsant effects of agents that produce temporal lobe-like seizures, such as kainic acid and pilocarpine. Males presented a higher amount of stronger seizures (full limbic convulsions) than females. Our results with pilocarpine also point toward a higher susceptibility of temporal lobe-like seizures in males compared to females. In the pilocarpine model, more males exhibited full limbic convulsions and status
Acknowledgements
The authors would like to thank Dr. Juan Carlos Jorge for proofreading the manuscript. This study was supported in part by an Institutional grant from the Deanship of Academic Affairs (CIDIC), Medical Sciences Campus–University of Puerto Rico (MSC-UPR) to A.C. Segarra, by NIH-NCRR-RCMI grants G12RR11126 and RR-03051 of the MSC-UPR by SNRP NINDS NS39408 to Dr. C.A. Jiménez-Rivera, and by RCMI GM-50695 to Universidad Central del Caribe (UCC). C.A. Mejı́as-Aponte was partially supported by the
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