Abstract
Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids—allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)—are known to modulate GABAA receptor-mediated transmission, thus playing a role in controlling neuronal network excitability. Given the role of GABAA signaling in epileptic disorders, neurosteroids have profound effects on seizure generation and play a role in the development of chronic epileptic conditions (i.e., epileptogenesis). We review here studies showing the effects induced by neurosteroids on epileptiform synchronization in in vitro brain slices, on epileptic activity in in vivo models, i.e., in animals that were made epileptic with chemoconvulsant treatment, and in epileptic patients. These studies reveal that neurosteroids can modulate ictogenesis and the occurrence of pathological network activity such as interictal spikes and high-frequency oscillations (80–500 Hz). Moreover, they can delay the onset of spontaneous seizures in animal models of mesial temporal lobe epilepsy. Overall, this evidence suggests that neurosteroids represent a new target for the treatment of focal epileptic disorders.
Highlights
Neurosteroids are a class of compounds that modulate neuronal excitability at the level of ion channels and membrane receptors [1,2,3]
An early in vitro study performed in rat hippocampal slices reported that the neurosteroid allopregnanolone (5α-pregnan-3α-ol-20-one), its 5β-epimer pregnanolone and pregnenolone sulfate can modulate the spontaneous interictal-like epileptiform discharges induced in the CA3 region by the GABAA receptor antagonist picrotoxin or the voltage-gated K+ channel blocker 4-aminopyridine (4AP) [32]. 4AP is known to indirectly enhance Ca2+ entry into presynaptic nerve terminals, increasing neurotransmitter release at both excitatory and inhibitory synapses
The same group performed further analyses of P450 cholesterol side chain cleavage (P450scc) immunoreactivity in the hippocampus of pilocarpine-treated rodents and found that it is expressed in several glial cells including astrocytes, oligodendrocytes and microglia [80]. They found that inhibition of neurosteroids with a daily administration of finasteride between day 4 and day 28 after status epilepticus (SE) could accelerate the development of spontaneous seizures, but only in animals that experienced an SE that lasted for more than 3 h and that exhibited significant increases of P450scc induction. In line with these findings, Joshi et al [81] used the lithium-pilocarpine model to demonstrate that a single administration of finasteride on the fourth day after a 2 h SE is sufficient to decrease the duration of the latent period; according to these authors, this suggests that inhibition of neurosteroids must be performed at the time of down-regulation of δ-GABA receptor expression, which occurs between SE and the onset of spontaneous seizures
Summary
Neurosteroids are a class of compounds that modulate neuronal excitability at the level of ion channels and membrane receptors [1,2,3]. They fall into three main classes, i.e., sulfated, pregnane, and androstane neurosteroids [4]. Given the role of GABA-mediated activity in epileptic disorders, pregnane neurosteroids can act as broad spectrum anti-convulsants [10,11,12,13,14,15,16,17] that modulate the efficacy of GABAA receptor function to enhance inhibition in the brain [18,19,20,21,22]. These studies lead us to conclude that neurosteroids may represent a new therapeutic target for the treatment of human focal epileptic disorders
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
