Neurosteroids

Abstract

This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone, and androstane neurosteroids, such as androstanediol and etiocholanone. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids increases both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-Areceptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.

GABAergic interneuron to astrocyte signalling: a neglected form of cell communication in the brain

“…Under pathological conditions, interneuron-astrocyte reciprocal interactions may also be affected. For example, it has been reported that astrocytes activated by an epileptogenic insult increase their synthetic machinery to produce neurosteroids, potent GABA A receptors modulators [106][107][108], that temporally prevent seizure generation and prolong the latent period in animal models of temporal lobe epilepsy [109].…”

Attention deficit hyperactivity disorder in children

“…Задержка созревания префронтальных отделов коры у детей с СДВГ является предпосылкой к формирова-нию импульсивности. В пубертатный период половые гормо-ны взаимодействуют с ГАМК-А и NMDA-рецепторами лим-бической системы и увеличивают эмоциональную неста-бильность и импульсивность [18,19]. Задержка созревания теменной и дорсолатеральной префронтальной коры отчасти обусловливает нарушение функций внимания [19].…”

The Impact of Gonadal Hormones on the Expression of Human Neurological Disorders

“…By acting as positive allosteric modulators of GABA-A receptors, allopregnanolone, THDOC and androstanediol augment GABAergic neurotransmission and thereby dampen neuronal excitability. Contrariwise, the sulfated neurosteroids may facilitate central excitation by curtailing GABAergic transmission and augmenting calcium flux through the NMDA (glutamate) receptor [5,6]. By impacting GABAergic and glutamatergic pathways, allopregnanolone and THDOC elicit sedative-hypnotic, anticonvulsant and anxiolytic effects relevant to the pathophysiology of epilepsy (see the section Reproductive Hormones and Epilepsy) and various mood disorders.…”

“…androstanediol and etiocholanone, metabolites of testosterone) and (c) sulfated neurosteroids (e.g pregnanolone sulfate and dehydroepiandrosterone sulfate). Neuroglial cells (astrocytes, oligodendrocytes) and certain neuronal populations are enriched for key enzymes (5α-reductase, 3α- hydroxysteroid oxidoreductase) which catalyze the interconversion of precursor hormones to neurosteroids [5,6,7]. Neurosteroids rapidly modulate neuronal firing by enhancing or attenuating inhibitory GABA-A receptor-mediated chloride (and other ion) conductance at the neuronal membrane.…”