Convulsant actions of the neurosteroid pregnenolone sulfate in mice

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

“…Levels of allopregnanolone, a major metabolite of progesterone, increase concurrently with progesterone over the course of gestation in both tissues and plasma (Gilbert Evans et al 2005). In the brain, allopregnanolone has positive modulatory actions at the g-aminobutyric acid type A (GABA A ) receptor, causing neuronal hyperpolarisation and inhibition of neural activity, resulting in anxiolytic (de Brito Faturi et al 2006), sedative (Paul & Purdy 1992) and anticonvulsant (Kokate et al 1999) effects. Allopregnanolone has also been shown to influence foetal arousal and sleep-wake activity in utero (Nicol et al 1997), demonstrating that synthesis and release of this steroid has a physiological and regulatory role within the central nervous system (CNS).…”

Characterization of the convulsant action of pregnenolone sulfate

“…The doses of PS required to produce seizures are lower than those reported in a previous study (Kokate et al, 1999b). In that study, performed on mice with intracerebroventricular infusion of PS, only behavioral seizures were measured and the dose necessary to induce seizures in 50% of the animals (CD 50 ) was 92 nmol and the threshold dose of PS for generating a seizure was 50 nmol.…”

“…It was recently demonstrated that PS enhances glutamate release from hippocampal neurons, but this effect occurs at 10 µM concentration PS (Meyer et al, 2002). These studies suggest that GABAergic neurotransmission is more sensitive to the effects of PS than glutamatergic neurotransmission and may account for the convulsant action of PS (Kokate et al, 1999b). Patterns of hippocampal epileptiform activity with increasing doses of PS.…”

“…However, even if PS diffused into a tissue volume of 0.1 ml, the local concentration of PS at the infusion site would be in the 10 µM-40 mM range, which clearly exceeds the concentrations required for modulation of both NMDA and GABA receptors on cultured pyramidal neurons. In the past, it was suggested that PS antagonism of GABA A receptors was more significant than enhancement of NMDA receptor function (Kokate et al, 1999b). This conclusion was based on the finding that systemic administration of benzodiazepines or neurosteroids blocked PS-induced seizures, while they are weak or ineffective against NMDA-induced seizures.…”

“…PS enhances convulsant potency of intraperitoneally administered NMDA in mice (Maione et al, 1992), chronic subcutaneous injections in rats significantly shifted the pentylenetetrazol dose-percent convulsions and latency curves to the left, and decreased the ED 50 of pentylenetetrazol for tonic convulsions (Reddy and Kulkarni, 1998). Intracerebroventricular administration of PS evoked limbic and tonic-clonic seizures in mice and potentiated the action of subconvulsive doses of intraperitoneally injected NMDA and pentylenetetrazol (Kokate et al, 1999b).…”