Neurosteroids and Seizure Activity

Abstract

Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline-pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3betamethylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebocontrolled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.

Characteristics of menstrual disorders and reproductive hormones in women with epilepsy at an Indonesian national referral hospital

“…Estradiol levels were reduced in WWE compared with those in WWoE in this study. In contrast, estrogen has both effects as pro- and anticonvulsant properties as well ( 28 ). Therefore, the lower level of estrogen could become the associated factors toward high frequency seizure in WWE and vice versa.…”

A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype

“…Endogenous neurosteroids are known for their seizure‐protective function by modulating GABA effects. 15 In the WT α4β3 receptor, 1 µM of the endogenous neurosteroid tetrahydrodeoxycorticosterone (or THDOC) potentiated submaximal and maximal GABA‐evoked responses. This potentiating effect was markedly reduced in α4T300Iβ3‐expressing cells (Figure 2C,E ).…”

Future opportunities for research in rescue treatments

“…52,53 In contrast, long-term (multi-day) seizure patterns have been observed in both male and female patients, 43 which could suggest that sex steroid fluctuations do not fully explain seizure patterns. Neurosteroids, such as allopregnanolone and tetrahydrodeoxycorticosterone, can alter γaminobutyric acid subtype A (GABA A ) receptor function, which can influence excessive neuroexcitation, 54 and low levels of allopregnanolone have been associated with seizure. 55 An approach to further elucidating relationships between hormones and seizures would be to sample hormone status in patients with RNS or subscalp EEG and to examine hormone levels during brain states of high and low seizure risk.…”