Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy

Abstract

This review highlights the role of major endogenous neurosteroids in seizure disorders and the promise of neurosteroid replacement therapy in epilepsy. Neurosteroids are endogenous modulators of seizure susceptibility. Neurosteroids such as allopregnanolone (3α-hydroxy-5α-pregnane-20-one) and allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one) are positive modulators of GABA-A receptors. Aside from peripheral tissues, neurosteroids are synthesized within the brain, mostly in principal neurons. Neurosteroids potentiate synaptic GABA-A receptor function and also activate δ-subunit-containing extrasynaptic GABA-A receptors that mediate tonic currents and thus may play an important role in neuronal network excitability and seizure susceptibility. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. They protect against seizures induced by GABA-A receptor antagonists, 6-Hz model, pilocarpine-induced limbic seizures, and seizures in kindled animals. Unlike benzodiazepines, tolerance does not occur to their actions during chronic administration. Our recent studies provide compelling evidence that neurosteroids may have antiepileptogenic properties. There is emerging evidence that endogenous neurosteroids may play a key role in the pathophysiology of catamenial epilepsy, stress-sensitive seizure conditions, temporal lobe epilepsy, and alcohol-withdrawal seizures. It is suggested that neurosteroid replacement with natural or synthetic neurosteroids may be useful in the treatment of epilepsy. Synthetic analogs of neurosteroids that are devoid of hormonal side effects show promise in the treatment of diverse seizure disorders. Agents that stimulate endogenous production of neurosteroids may also be useful for treatment of epilepsy.

Keywords: GABA-A receptor; THDOC; allopregnanolone; catamenial epilepsy; epilepsy; epileptogenesis; neurosteroids; seizure.

Figure 1

Chemical structures of major endogenous neurosteroids. THDOC differs from allopregnanolone by a 21β-hydroxyl group, while androstanediol differs from allopregnanolone by a 17β-hydroxyl group instead of 17β-methyl-carbonyl group. Synthetic analogs of neurosteroids are prepared by additional moieties at C3-position (e.g., ganaxolone), C2- and C11-positions (alphaxolone), and C11-position (minaxolone).

Figure 2

Neurosteroid modulation of synaptic and extrasynaptic GABA-A receptors. Postsynaptic GABA-A receptors, which are pentameric chloride channels composed of 2α2βγ subunits, mediate the phasic portion of GABAergic inhibition, while extrasynaptic GABA-A receptors, pentamers composed of 2α2βδ subunits, primarily contribute to tonic inhibition in the hippocampus. Neurosteroids activate both synaptic and extrasynaptic receptors and enhance the phasic and tonic inhibition. Therefore, they may promote effective inhibition of seizures. Two different strategies – concomitant augmentation of both phasic and tonic inhibition and selective augmentation of tonic inhibition − are being tested in epilepsy models.

Figure 3

Role of neurosteroids in the limbic epileptogenesis. (A) Rapid kindling. Mice treated with the neurosteroid precursor progesterone (P) displayed marked retardation of rapid hippocampus epileptogenesis, as expressed by a slower rate of kindling development for stage 5 seizures. P’s inhibition of kindling epileptogenesis was blocked by finasteride. P (25 mg/kg, sc) was given 30-min prior to stimulation sessions and finasteride (50 mg/kg, ip) was injected 1 h before P treatment. *p < 0.01 vs. vehicle control, #p < 0.01 vs. P treatment alone. Adapted from Reddy and Mohan (2011). (B) Regular kindling. Rate of kindling (number of stimulations required to elicit behavioral stage 5 seizures) was significantly delayed in progesterone-treated animals. Progesterone (25 mg/kg, sc) was given 30-min prior to stimulation sessions. Adapted from Reddy et al. (2010).