Progesterone receptor activation regulates seizure susceptibility

Abstract

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.

Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

“…Progesterone exerts anticonvulsant effects in animal epilepsy models through a PR-independent mechanism as they are not decreased in PR knockout (PRKO) mice ( 19 ). Instead, progesterone's anticonvulsant potency is increased in PRKO mice which is consistent with results showing activation of PR in a status epilepticus rat model increases seizure frequency ( 19 , 20 ). Progesterone's antiseizure actions are dependent on its conversion to allopregnanolone since cotreatment with the 5α-reductase inhibitor, finasteride, blocks progesterone's actions ( 19 ).…”

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

“…We explored neurosteroid levels in the brain as a possible mechanism involved in the rebound effect, since it has been reported that administration of progesterone is followed by a rebound effect with the 2-fold increase in seizure frequency after abrupt interruption of treatment [ 19 ]. This suggested that changes in brain neurosteroid levels could be accompanied by corresponding alterations in the seizure occurrence.…”

“…Indeed, neurosteroids have been implicated in a phenomenon similar to the rebound effect in epileptic female rats treated with progesterone for a week, in which a 2-fold increase in the seizure frequency occurred in 57% of animals in the week following progesterone withdrawal. Notably, this effect was independent of progesterone receptor activation and probably was due to the conversion of progesterone to other neurosteroids [ 19 ].…”

Limbic progesterone receptor activity enhances neuronal excitability and seizures

“…Perimenstrual seizure exacerbation was thought to be due to progesterone withdrawal, but exogenous progesterone was not efficacious in treating these seizures in the majority of patients with catamenial epilepsy in a recent clinical trial 18 . The findings of our recent studies suggest that PR‐regulated effects of progesterone could contribute to catamenial seizures 9, 10 …”

“…Prior studies utilizing drugs to activate and block PRs suggested that PR activation enhances excitatory transmission and worsens seizures. The PR antagonist Ru‐486 suppressed seizures in epileptic animals, 9 whereas Nestorone (16‐methylene‐17 alpha‐acetoxy‐19‐nor‐pregn‐4‐ene‐3,20‐dione), a specific PR agonist, increased seizures 10 . Progesterone via PRs potentiates glutamatergic neurotransmission and enhances α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) expression in the CA1 hippocampus 9 .…”