A novel therapeutic approach for treatment of catamenial epilepsy

Joshi, Suchitra; Sun, Huayu; Rajasekaran, Karthik; Williamson, John; Perez‐Reyes, Edward; Kapur, Jaideep

doi:10.1016/j.nbd.2017.12.009

Cited by 42 publications

(67 citation statements)

References 70 publications

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“…Status epilepticus (SE) was induced in adult Sprague‐Dawley female rats (200–220 g) using the lithium‐pilocarpine method as described previously . Thirty days after SE, animals were implanted with bilateral subdural cortical electrodes, a bipolar left hippocampal electrode, and a cerebellar reference electrode . Following seven days of recovery from surgery, continuous video‐EEG monitoring was started and performed as described in our earlier studies .…”

Section: Methodsmentioning

confidence: 99%

“…Thirty days after SE, animals were implanted with bilateral subdural cortical electrodes, a bipolar left hippocampal electrode, and a cerebellar reference electrode . Following seven days of recovery from surgery, continuous video‐EEG monitoring was started and performed as described in our earlier studies . Seizures are characterized by temporally evolving high frequency, high amplitude rhythmic discharges followed by a brief suppression of EEG and various criteria have been used to define seizures in the past .…”

Section: Methodsmentioning

confidence: 99%

“…We found previously that RU‐486 treatment reduced neurosteroid withdrawal‐induced seizures in an animal model . Since RU‐486 is a potent progesterone receptor (PR) antagonist, this previous study raised the possibility that PR activation regulates seizure frequency.…”

Section: Introductionmentioning

confidence: 99%

“…The existing animal model of catamenial epilepsy, which we used in our prior study, involved treating animals with the Pregnant Mare Serum Gonadotropin (PMSG) and human chorionic gonadotropin (β‐HCG) hormones to increase serum progesterone levels . However, these hormones, particularly β‐HCG, may exert additional effects due to their structural similarity to luteinizing hormone .…”

Section: Introductionmentioning

confidence: 99%

“…However, these hormones, particularly β‐HCG, may exert additional effects due to their structural similarity to luteinizing hormone . Seizure exacerbation was also triggered by finasteride treatment, which causes neurosteroid withdrawal rather than progesterone withdrawal . Since finasteride treatment increases progesterone levels, it may also exert additional effects.…”

Section: Introductionmentioning

confidence: 99%

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Progesterone receptor activation regulates seizure susceptibility

Shiono

Williamson

Joshi

2019

Ann Clin Transl Neurol

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Objective Progesterone is a potent neuromodulator that exerts effects on the brain through neurosteroids, progesterone receptors (PRs), and other molecules. Whether PR activation regulates seizures is not known. We determined whether PR activation increased seizure susceptibility. Methods Adult female rats that developed epilepsy following lithium‐pilocarpine‐induced status epilepticus (SE) were used. Seizures were recorded by continuous‐video EEG and read by an individual blinded to the treatment of the animals. The animals were treated for a week with progesterone (50 mg/kg per day), and the effect of progesterone withdrawal on seizure frequency was assessed during the subsequent week. During the week of progesterone treatment, the animals were treated with PR antagonist RU‐486 (10 mg/kg per day) or a vehicle control, which was administered 30 min before progesterone. In another set of animals, we determined the effect of the PR agonist Nestorone (3 mg/kg per day) on seizure frequency. The animals were treated with Nestorone or vehicle for a week, and seizure frequencies at baseline and during the treatment week were compared. Results Progesterone withdrawal induced twofold increase in seizures in 57% of animals (n = 14). RU‐486 treatment in combination with progesterone, prevented this increase, and a smaller fraction of animals (17%) experienced withdrawal seizures (n = 13). The specific activation of PRs by Nestorone also increased the seizure frequency. Forty‐six percent (n = 14) of Nestorone‐treated animals experienced at least a 50% increase in seizures compared to only 9% of the vehicle‐treated animals (n = 11). Interpretation PR activation increased seizure frequency in epileptic animals. Thus, PRs may be novel targets for treating catamenial epilepsy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Progesterone receptor activation regulates seizure susceptibility

Shiono

Williamson

Joshi

2019

Ann Clin Transl Neurol

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Reduced neurosteroid potentiation of GABA_A receptors in epilepsy and depolarized hippocampal neurons

Joshi

Roden²,

Jansen

2020

Ann Clin Transl Neurol

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Objective: Neurosteroids regulate neuronal excitability by potentiating caminobutyric acid type-A receptors (GABARs). In animal models of temporal lobe epilepsy, the neurosteroid sensitivity of GABARs is diminished and GABAR subunit composition is altered. We tested whether similar changes occur in patients with epilepsy and if depolarization-induced increases in neuronal activity can replicate this effect. Methods: We determined GABAR a4 subunit expression in cortical tissue resected from pediatric epilepsy patients. Modulation of human GABARs by allopregnanolone and Ro15-4513 was measured in Xenopus oocytes using whole-cell patch clamp. To extend the findings obtained using tissue from epilepsy patients, we evaluated GABAR expression and modulation by allopregnanolone and Ro15-4513 in cultured rat hippocampal neurons exposed to high extracellular potassium (HK) to increase neuronal activity. Results: Expression of a4 subunits was increased in pediatric cortical epilepsy specimens encompassing multiple pathologies. The potentiation of GABA-evoked currents by the neurosteroid allopregnanolone was decreased in Xenopus oocytes expressing GABARs isolated from epilepsy patients. Furthermore, receptors isolated from epilepsy but not control tissue were sensitive to potentiation by Ro15-4513, indicating higher expression of a 4 b x c 2 subunit-containing receptors. Correspondingly, increasing the activity of cultured rat hippocampal neurons reduced allopregnanolone potentiation of miniature inhibitory postsynaptic currents (mIPSCs), increased modulation of tonic GABAR current by Ro15-4513, upregulated the surface expression of a4 and c2 subunits, and increased the colocalization of a4 and c2 subunit immunoreactivity. Interpretation: These findings suggest that seizure activity-induced upregulation of a 4 b x c 2 subunit-containing GABARs could affect the anticonvulsant actions of neurosteroids.

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Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low‐dose kainic acid systemic injection paradigm in mice

Lawande,

Conklin,

Christian‐Hinman

2023

Epilepsia Open

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Objective:Sex differences in epilepsy appear driven in part due to effects of gonadal steroids, with varying results in experimental models based on species, strain, and method of seizure induction. Furthermore, removing a main source of these steroids via gonadectomy may impact seizure characteristics differently in males and females. Repeated low‐dose kainic acid (RLDKA) systemic injection paradigms were recently shown to reliably induce status epilepticus (SE) and hippocampal histopathology in C57BL/6J mice. Here, we investigated whether seizure susceptibility in a RLDKA injection protocol exhibits a sex difference, and whether gonadectomy differentially influences response to this seizure induction paradigm in males and females.Methods:Adult C57BL/6J mice were left gonad‐intact as controls or gonadectomized (females: ovariectomized, OVX; males: orchidectomized, ORX). At least 2 weeks later, KA was injected i.p. every 30 minutes at 7.5 mg/kg or less until the animal reached SE, defined by at least 5 generalized seizures (GS, Racine stage 3 or higher). Parameters of susceptibility to GS induction, SE development, and mortality rates were quantified.Results:No differences in seizure susceptibility or mortality were observed between control males and control females. Gonadectomized mice exhibited increased susceptibility and reduced latency to both GS and SE in comparison to corresponding controls of the same sex, but the effects were stronger in males. In addition, ORX males, but not OVX females, exhibited strongly increased seizure‐induced mortality.Significance:The RLDKA protocol is notable for its efficacy in inducing SE and seizure‐induced histopathology in C57BL/6J mice, the background for many transgenic strains in current use in epilepsy research. The present results indicate that this protocol may be beneficial for investigating the effects of gonadal hormone replacement on seizure susceptibility, mortality, and seizure‐induced histopathology, and that gonadectomy unmasks sex differences in susceptibility to seizures and mortality not observed in gonad‐intact controls.

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A novel therapeutic approach for treatment of catamenial epilepsy

Cited by 42 publications

References 70 publications

Progesterone receptor activation regulates seizure susceptibility

Progesterone receptor activation regulates seizure susceptibility

Reduced neurosteroid potentiation of GABA_A receptors in epilepsy and depolarized hippocampal neurons

Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low‐dose kainic acid systemic injection paradigm in mice

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A novel therapeutic approach for treatment of catamenial epilepsy

Cited by 42 publications

References 70 publications

Progesterone receptor activation regulates seizure susceptibility

Progesterone receptor activation regulates seizure susceptibility

Reduced neurosteroid potentiation of GABAA receptors in epilepsy and depolarized hippocampal neurons

Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low‐dose kainic acid systemic injection paradigm in mice

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Reduced neurosteroid potentiation of GABA_A receptors in epilepsy and depolarized hippocampal neurons