Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis

Abstract

Progesterone (P) is an endogenous anticonvulsant hormone. P is being evaluated as a treatment for epilepsy, traumatic brain injury, and other complex neurological conditions. Preclinical and clinical studies suggest that P appears to interrupt epileptogenic events. However, the potential disease-modifying effect of P in epileptogenic models is not widely investigated. In this study, we examined the effects of P on the development of hippocampus kindling in female mice. In addition, we determined the role of progesterone receptors (PR) in the P’s effect on the kindling epileptogenesis utilizing PR knockout (PRKO) mice. P, at 25 mg/kg, did not affect seizures and did not exert sedative/motor effects in fully-kindled mice. P treatment (25 mg/kg, twice daily for 2 weeks) significantly suppressed the rate of development of behavioral kindled seizure activity evoked by daily hippocampus stimulation in wild-type (WT) mice, indicating a disease-modifying effect of P on limbic epileptogenesis. There was a significant increase in the rate of ‘rebound or withdrawal’ kindling during drug-free stimulation sessions following abrupt discontinuation of P treatment. A washout period after termination of P treatment prevented such acceleration in kindling. PRKO mice were kindled significantly slower than WT mice, indicating a modulatory role of PRs in seizure susceptibility. P’s effects on early kindling progression was partially decreased in PRKO mice, but the overall (~2-fold) delay in the rate of kindling for the induction of stage 5 seizures was unchanged in PRKO mice. Moreover, the acute anticonvulsant effect of P was undiminished in fully-kindled PRKO mice. These studies suggest that P exerts disease-modifying effects in the hippocampus kindling model at doses that do not significantly affect seizure expression and motor performance, and the kindling-retarding effects of P may occur partly through a complex PR-dependent and PR-independent mechanism.

Neurosteroids and their role in sex-specific epilepsies

“…In recent years, numerous studies have confirmed the powerful anticonvulsant activity of progesterone in diverse animal seizure models (see Reddy, 2009). Recent studies in our lab confirm the antiepileptogenic effects of progesterone in the kindling model of epileptogenesis (Reddy et al, 2010; Reddy and Mohan, 2011). There are two mechanisms by which progesterone affects reproduction and seizure susceptibility: binding to progesterone receptors (PRs) and being metabolized to the neurosteroid allopregnanolone.…”

“…Recent studies suggest that neurosteroids play a role in epileptogenesis (Edwards et al, 2001; Biagini et al, 2006; 2009a; 2010; Reddy et al, 2010; Reddy, 2013a). Using the kindling model, we demonstrated that the development and persistence of limbic epileptogenesis are impaired in mice lacking progesterone receptors (Reddy and Mohan, 2011).…”

Clinical Potential of Neurosteroids for CNS Disorders

“…In contrast to benzodiazepines, where utility in the chronic treatment of epilepsy is limited by tolerance, anticonvulsant tolerance is not evident with neurosteroids [56, 57]. Recent studies suggest that neurosteroids play a role in epileptogenesis [58, 59]. Thus, there is considerable interest in leveraging the growing understanding of neurosteroid modulation of GABA-A receptor function to mitigate epilepsy symptomatology.…”

“…It has been shown that functional inactivation of synaptic GABA-A receptors via active internalization is the physiologic mechanism by which benzodiazepine resistance rapidly emerges in refractory SE [79, 80]. Therefore, neurosteroid compounds like AP and its synthetic derivatives, which potentiate both phasic and tonic current, have been proposed as potential alternatives [12, 58, 81]. A randomized, double-blind, placebo-controlled, add-on, Phase II clinical trial is underway to evaluate SGE-102, an intravenous formulation of AP [82].…”

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

“…Progesterone is a neurosteroid that could potentially have immunosuppression effects and contributions to neuronal excitability changes; firing to neurotransmitters are suppressed [131]. Current findings have suggested benefits mostly in females with decreases in spike frequency [132]. …”