GnRH-immunoreactive fiber changes with unilateral amygdala-kindled seizures
Introduction
Reproductive dysfunction is unusually common among women with temporolimbic epilepsy (TLE) (Herzog and Friedman, 2002) and can usually be related to reproductive endocrine disorders (Herzog et al., 1986; Herzog, 1989, Herzog, 1997). Involvement of mesial temporolimbic structures with epileptiform discharges may disrupt the orderly pulsatile secretion of gonadotropin releasing hormone (GnRH) (Drislane et al., 1994; Herzog et al., 2000; Quigg et al., 2002). Altered hypothalamopituitary regulation of ovarian secretion may promote the development of reproductive endocrine disorders. Different reproductive endocrine disorders may be associated with unilateral left and right-sided foci (Herzog, 1993). Specifically, polycystic ovarian syndrome (PCOS) may occur more frequently with left lateral discharges. Hypothalamic amenorrhea (HA) may be more common with right lateral discharges.
The amygdala, a common site of involvement in TLE, has massive direct reciprocal anatomic connections with the ventromedial hypothalamus that is involved in the regulation, production and secretion of GnRH (Zolovick, 1972). Amygdala kindling can produce reproductive endocrine changes and disruption of the estrus cycle in female rats (Edwards et al., 1999). Disruption of the GnRH system may be a factor. Hypothalamic GnRH fiber staining is diminished in a pilocarpine model (Amado et al., 1993). Furthermore, unilateral amygdala kindling activates reproductive endocrine hypothalamic nuclei ipsilaterally more than contralaterally as suggested by fos staining in the female rat (Silveira et al., 2000). Since GnRH content and regulation of reproductive and sexual function differs between the left and right sides of the hypothalamus (Gerendai et al., 1978), laterally asymmetric activation of the reproductive neuroendocrine system by seizures may be a factor in the development of different reproductive endocrine disorders with left and right sided temprolimbic epilepsy.
The purpose of this investigation was to carry out a preliminary evaluation of this postulated mechanism. Specifically, this investigation assessed whether unilateral amygdala-induced seizures are associated with a change in the number and lateral distribution of GnRH-staining fibers in the ventromedial hypothalamus using a focal kainic acid (KA) injection female rat model of epilepsy. We chose to focus on the ventrolateral part of the ventromedial hypothalamic nucleus (VMHVL), a sexually dimorphic region that is known to be important in the regulation of reproductive function.
Section snippets
Methods
Twenty-two Sprague–Dawley adult female rats, weighing 220–300 g, were used in this study. Four microliters unilateral injections of kainic acid (0.5 μg/μl, ten animals) or saline (seven animals) were placed in the amygdala using the following stereotaxic coordinates (Paxinos and Watson, 1986): 2.8 mm posterior to the bregma, 5.0 mm lateral to the midline, and 8.2 mm below the skull.
Animals were observed for up to 4 h after the injection, and then periodically for 4 weeks. In the experimental
Results
Generalized convulsive seizures occurred in all experimental animals following KA injection but in none of the saline injected or naı̈ve control animals. Spontaneous recurrent seizures, consisting of motor arrest and staring episodes, were occasionally seen in the KA animals over the 4-week observation period. Unilateral amygdaloid lesions developed in all KA animals (Fig. 1, Fig. 2). There was no evidence on cresyl violet staining that the lesions in the KA animals were bilateral or
Discussion
Amado et al. reported a generalized yet selective reduction in the density of hypothalamic GnRH-immunoreactive fibers following intraperitoneal pilocarpine administration in a female rat epilepsy model. The density reduction was noted at two time intervals, 10–15 days and 60–90 days. Their study showed that GnRH fiber staining loss was quite selective following pilocarpine-induced seizures since galanin staining did not show a significant difference in the number and size of perikarya between
Acknowledgements
Supported by a Winokur Foundation Grant.
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Mechanisms linking neurological disorders with reproductive endocrine dysfunction: Insights from epilepsy research
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2019, SeizureCitation Excerpt :It is noteworthy that both primary generalized [15] and focal onset [16] epilepsy can alter gonadotropin releasing hormone (GnRH) pulsatility. In focal onset epilepsy, moreover, there is a lateralized asymmetry in this modulation such that the directional change in pulse frequency relates to the laterality of the epileptic focus [16–18]. Since the development of normal GnRH pulsatility is a prerequisite for the establishment of menarche and ovulatory cycles, it is then possible that epilepsy may alter these processes.
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2013, The Lancet NeurologyCitation Excerpt :The GnRH-cell population is vulnerable to injury by seizures. In female rats with seizures induced by local injection of kainic acid into the amygdala, ipsilateral loss of GnRH-staining fibres in the hypothalamus was noted.27,28 Lateralisation of temporal lobe epilepsy seems to be associated with specific types of reproductive dysfunction.
Pilocarpine-induced status epilepticus and subsequent spontaneous seizures: Lack of effect on the number of gonadotropin-releasing hormone-positive neurons in a mouse model of temporal lobe epilepsy
2012, NeuroscienceCitation Excerpt :The discrepancy in the data of the present study with those of Amado et al. (1993) and Friedman et al. (2002) may reflect methodological differences including, but not limited to, the procedures for preparation of the animal model of epilepsy, the GnRH antibody, the nature of the histopathological observations (e.g. axonal fibers vs. cell bodies), and the procedures for quantification of the data. For example, Friedman et al. (2002) quantified GnRH-positive fibers from two sections in one area of GnRH distribution (ventromedial hypothalamus), and Amado et al. (1993) quantified fibers from every third section. The focus on GnRH fibers and the lower sample numbers in the previous studies, compared with the present studies aimed primarily at counting neuronal cell bodies, may have resulted in false positives by Amado et al. (1993) and Friedman et al. (2002), owing to intra- and inter-animal variations in the distribution of GnRH neurons and fibers.
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