Gonadectomy unmasks an inhibitory effect of progesterone on amygdala kindling in male rats

doi:10.1016/S0006-8993(00)03147-4

Brain Research

Volume 889, Issues 1–2, 19 January 2001, Pages 260-263

https://doi.org/10.1016/S0006-8993(00)03147-4 Get rights and content

Abstract

Previous studies have suggested that the effects of progesterone on kindling in rats may be sexually differentiated, significant effects of physiological levels of progesterone being observed only in females. The present study demonstrates that this difference results from the hormones secreted by the testes. Thus, in orchidectomized males, progesterone induces a delay in the onset of amygdala-kindled seizures similar to that observed in females.

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Acknowledgements

The authors would like to thank Antonio Mendonca for his invaluable assistance in stereotaxic surgery and Jerome Chang for his assistance in histologic sectioning of the brains. Partial financial support was provided by a grant from the Bloorview Children’s Hospital Foundation to W.M.B., and grants from the Natural Sciences and Engineering Research Council of Canada to N.J.M. and H.E.E.

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Sex differences in the developing brain impact stress-induced epileptogenicity following hyperthermia-induced seizures
2021, Neurobiology of Disease
Citation Excerpt :
Similarly, increased kindling rates were also observed in adult male rats pre-exposed to chronic postnatal cross-fostering stress during a similar period (i.e., P1-P23) (Gilby et al., 2009). Furthermore, in adult female rats, adrenalectomy compared to CORT replacement or sham-operated controls can delay the kindling process, while testosterone in males can enhance it (Edwards et al., 2001; Edwards et al., 1999). However, it should also be noted that certain circumstances do lead to increased seizure susceptibility in females more than males.
Febrile seizures (FS) are common, affecting 2–5% of children between the ages of 3 months and 6 years. Complex FS occur in 10% of patients with FS and are strongly associated with mesial temporal lobe epilepsy. Current research suggests that predisposing factors, such as genetic and anatomic abnormalities, may be necessary for complex FS to translate to mesial temporal lobe epilepsy. Sex hormones are known to influence seizure susceptibility and epileptogenesis, but whether sex-specific effects of early life stress play a role in epileptogenesis is unclear. Here, we investigate sex differences in the activity of the hypothalamic–pituitary–adrenal (HPA) axis following chronic stress and the underlying contributions of gonadal hormones to the susceptibility of hyperthermia-induced seizures (HS) in rat pups. Chronic stress consisted of daily injections of 40 mg/kg of corticosterone (CORT) subcutaneously from postnatal day (P) 1 to P9 in male and female rat pups followed by HS at P10. Body mass, plasma CORT levels, temperature threshold to HS, seizure characteristics, and electroencephalographic in vivo recordings were compared between CORT- and vehicle (VEH)-injected littermates during and after HS at P10. In juvenile rats (P18-P22), in vitro CA1 pyramidal cell recordings were recorded in males to investigate excitatory and inhibitory neuronal circuits. Results show that daily CORT injections increased basal plasma CORT levels before HS and significantly reduced weight gain and body temperature threshold of HS in both males and females. CORT also significantly lowered the generalized convulsions (GC) latency while increasing recovery time and the number of electrographic seizures (>10s), which had longer duration. Furthermore, sex-specific differences were found in response to chronic CORT injections. Compared to females, male pups had increased basal plasma CORT levels after HS, longer recovery time and a higher number of electrographic seizures (>10s), which also had longer duration. Sex-specific differences were also found at baseline conditions with lower latency to generalized convulsions and longer duration of electrographic seizures in males but not in females. In juvenile male rats, the amplitude of evoked excitatory postsynaptic potentials, as well as the amplitude of inhibitory postsynaptic currents, were significantly greater in CORT rats when compared to VEH littermates. These findings not only validate CORT injections as a stress model, but also show a sex difference in baseline conditions as well as a response to chronic CORT and an impact on seizure susceptibility, supporting a potential link between sustained early-life stress and complex FS. Overall, these effects also indicate a putatively less severe phenotype in female than male pups. Ultimately, studies investigating the biological underpinnings of sex differences as a determining factor in mental and neurologic problems are necessary to develop better diagnostic, preventative, and therapeutic approaches for all patients regardless of their sex.
Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus
2019, Neuroscience Letters
Female sex hormone, progesterone, in addition to seizure modifying activity is also known as a potential protective agent against various brain injury conditions. Considering the predisposal role of traumatic brain injury (TBI) on developing post-traumatic epilepsy (PTE), the effect of progesterone on post-traumatic epileptogenesis is not investigated yet. Male Wistar rats were given a moderate focal weight drop injury (500 gr) or sham surgery and then progesterone (16 and 32mg/kg) was given daily for two consecutive weeks. On day 15 of injury, seizures were induced by administration of a GABAA receptor antagonist, pentylenetetrazole (PTZ, 30 mg/kg). Seizures were then assessed over a 1-h period using the Racine clinical rating scale.
Traumatized animals that received 32 mg/kg progesterone had reduced score, duration of seizures and almost did not show tonic-clonic seizures during 60 min versus the untreated trauma group. In line with behavioral alterations, 32 mg/kg progesterone enhanced the amount of Nrf2 and HO-1 proteins and decreased the level of NF-kB, BDNF, Caspase 3 and ratio of Bax/Bcl-2 in the ipsilateral hippocampus. Additionally, the number of TUNEL-positive apoptotic cells, as well as injured dark neurons in the parietal cortex and hippocampal CA1 of 32 mg/kg-treated animals showed a significant reduction. Administration of 16 mg/kg progesterone elevated production of BDNF, Bax and Caspase 3 and decreased anti-apoptotic Bcl-2 protein. Taken together, an early administration of 32 mg/kg of progesterone after TBI for two weeks post-injury modified seizure activity.
Our findings suggest that post-traumatic anti-epileptogenesis property of a high dose of progesterone partly occurs through the manipulation of BDNF-TrkB axis along with control of cell survival pathways.
Neurosteroid regulation of GABA<inf>A</inf> receptors: A role in catamenial epilepsy
2019, Brain Research
The female reproductive hormones progesterone and estrogen regulate network excitability. Fluctuations in the circulating levels of these hormones during the menstrual cycle cause frequent seizures during certain phases of the cycle in women with epilepsy. This seizure exacerbation, called catamenial epilepsy, is a dominant form of drug-refractory epilepsy in women of reproductive age. Progesterone, through its neurosteroid derivative allopregnanolone, increases γ-aminobutyric acid type-A receptor (GABAR)-mediated inhibition in the brain and keeps seizures under control. Catamenial seizures are believed to be a neurosteroid withdrawal symptom, and it was hypothesized that exogenous administration of progesterone to maintain its levels high during luteal phase will treat catamenial seizures. However, in a multicenter, double-blind, phase III clinical trial, progesterone treatment did not suppress catamenial seizures. The expression of GABARs with reduced neurosteroid sensitivity in epileptic animals may explain the failure of the progesterone clinical trial. The expression of neurosteroid-sensitive δ subunit-containing GABARs is reduced, and the expression of α4γ2 subunit-containing GABARs is upregulated, which alters the inhibition of dentate granule cells in epilepsy. These changes reduce the endogenous neurosteroid control of seizures and contribute to catamenial seizures.
Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy
2017, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
In the pilocarpine model, rats develop seizures after a latent period that mirrors that of P450scc elevation, and treatment with finasteride (a neurosteroid synthesis inhibitor) is capable of reducing latency-to-seizure expression after SE, as well as exacerbating seizure intensity [215]. Neurosteroid administration has been shown to exert powerful anticonvulsant action in a number of animal seizure models [216], and ongoing research has provided evidence of endogenous neurosteroids' potential role in modulating epileptogenesis [161,162,215,217,]. Neurosteroids have been used to successfully inhibit seizures induced by PTZ, bicuculline, pilocarpine, and evoked seizures in kindling paradigms [148,216–222].
This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982–2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy.
Neurosteroids and their role in sex-specific epilepsies
2014, Neurobiology of Disease
Citation Excerpt :
Unlike benzodiazepines, neurosteroids are able to modulate all isoforms of GABA-A receptors, including those that contain benzodiazepine-insensitive α4 and α6 subunits or lack the obligatory γ2 subunit required for benzodiazepine-sensitivity. Recent studies suggest that neurosteroids play a role in epileptogenesis (Biagini et al., 2006, 2009, 2010; Edwards et al., 2001; Reddy, 2013a; Reddy et al., 2010). Using the kindling model, we demonstrated that the development and persistence of limbic epileptogenesis are impaired in mice lacking progesterone receptors (Reddy and Mohan, 2011a, 2011b).
Neurosteroids are involved in sex-specific epilepsies. Allopregnanolone and related endogenous neurosteroids in the brain control excessive neuronal excitability and seizure susceptibility. Neurosteroids activate GABA-A receptors, especially extrasynaptic αγδ-GABA-A receptor subtypes that mediate tonic inhibition and thus dampen network excitability. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. Neurosteroids also exert antiepileptogenic effects. There is emerging evidence on a critical role for neurosteroids in the pathophysiology of the sex-specific forms of epilepsies such as catamenial epilepsy, a menstrual cycle-related seizure disorder in women. Catamenial epilepsy is a neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around the perimenstrual or periovulatory period. Apart from ovarian hormones, fluctuations in neurosteroid levels could play a critical role in this gender-specific epilepsy. Neurosteroids also regulate the plasticity of synaptic and extrasynaptic GABA-A receptors in the hippocampus and other regions involved in epilepsy pathology. Based on these studies, we proposed a neurosteroid replacement therapy for catamenial epilepsy. Thus, neurosteroids are novel drug targets for pharmacotherapy of epilepsy.
Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis
2012, Epilepsy and Behavior
Progesterone (P) plays an important role in seizure susceptibility in women with epilepsy. Preclinical and experimental studies suggest that P appears to interrupt epileptogenesis, which is a process whereby a normal brain becomes progressively susceptible to recurrent, unprovoked seizures due to precipitating risk factors. Progesterone has not been investigated widely for its potential disease-modifying activity in epileptogenic models. Recently, P has been shown to exert disease-modifying effects in the kindling model of epileptogenesis. However, the mechanisms underlying the protective effects of P against epileptogenesis remain unclear. In this study, we investigated the role of P-derived neurosteroids in the disease-modifying activity of P. It is hypothesized that 5α-reductase converts P to allopregnanolone and related neurosteroids that retard epileptogenesis in the brain. To test this hypothesis, we utilized the mouse hippocampus kindling model of epileptogenesis and investigated the effect of finasteride, a 5α-reductase and neurosteroid synthesis inhibitor. Progesterone markedly retarded the development of epileptogenesis and inhibited the rate of kindling acquisition to elicit stage 5 seizures. Pretreatment with finasteride led to complete inhibition of the P-induced retardation of the limbic epileptogenesis in mice. Finasteride did not significantly influence the acute seizure expression in fully kindled mice expressing stage 5 seizures. Thus, neurosteroids that potentiate phasic and tonic inhibition in the hippocampus, such as allopregnanolone, may mediate the disease-modifying effect of P, indicating a new role of neurosteroids in acquired limbic epileptogenesis and temporal lobe epilepsy.

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Short communicationGonadectomy unmasks an inhibitory effect of progesterone on amygdala kindling in male rats

Abstract

Section snippets

Acknowledgements

Brain Res.

Brain Res.

Pharmacol. Biochem. Behav.

Psychoneuroendocrinology

Epilepsy Res.

Brain Res.

Brain Res.

Epilepsy Res.

Brain Res.

The ontogeny of sex differences in estrogen-induced progesterone receptors in rat brain

Endocrinology

Short communication
Gonadectomy unmasks an inhibitory effect of progesterone on amygdala kindling in male rats