Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy

Excerpt

Certain steroid hormone metabolites that have activity as modulators of GABA_A receptors but lack conventional hormonal effects—including allopregnanolone and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly in principle (excitatory) neurons, and also in peripheral tissues. At low concentrations, such neurosteroids potentiate GABA_A receptor currents, whereas at higher concentrations they directly activate the receptor; large magnitude effects occur on nonsynaptic δ subunit-containing GABA_A receptors that mediate tonic currents. GABA_A receptor modulatory neurosteroids confer seizure protection in diverse animal models, without tolerance during chronic administration. Endogenous neurosteroids may play a role in catamenial epilepsy, stress-induced changes in seizure susceptibility, temporal lobe epilepsy, and alcohol withdrawal seizures. Moreover, neurosteroid replacement with natural or synthetic neurosteroids may be useful in these conditions and more generally in the treatment of partial seizures. Ganaxolone, the synthetic 3β-methyl analog of allopregnanolone, has been evaluated in clinical trials for the treatment of epilepsy. It appears to be an efficacious, well-tolerated and safe treatment for partial seizures. Neurosteroids and analogs such as ganaxolone show promise in the treatment of diverse forms of epilepsy.