Neurosteroid regulation of central nervous system development

Abstract

Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABA A and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids -pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone.

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

“…Negative GABA A regulators include the sulphated derivatives of pregnenolone and DHEA as well as the 3a,5a-and 3a,5b-reduced metabolites of cortisol (Morrow 2007). Other neuroactive steroids (such as pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone) are attributed with actions in central nervous system (CNS) development (Mellon 2007). The debate about the origin of the DOC precursor for its neuroactive THDOC metabolite continues, but although steroidogenesis, and the production of the steroid regulators of GABA has been reported in the CNS (Morrow 2007), it is still likely that the adrenal is an important source (Boyd et al 2010, Kaufman et al 2010).…”

Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells

“…Starting from these data, neuroactive steroids have received great attention as autocrine and paracrine regulators of brain function. Neurosteroids are a class of neuroactive compounds involved in CNS development, in adult brain functionality and in neuroprotection [10][11][12][13]. The absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioural disorders and neurodegeneration [13].…”

Extra-Adrenal Glucocorticoid Synthesis in Mucosal Tissues and Its Implication in Mucosal Immune Homeostasis and Tumor Development

“…Among the locally synthesized and active steroids are pregnenolone and pregnenolone sulphate, progesterone, allopregnanolone, dehydroepiandrosterone and dehydroepiandrosterone sulphate. These steroids can exert their effects in neurogenesis, development, myelinization, memory, reactions to stress through engaging nuclear receptors and modulating transcription, as well as affecting neurotransmission by modifying the activity of gamma-aminobutiric acid (GABAA), N-methyl-D-aspartic acid (NMDA), and sigma receptors (for review [31,32,68]). Low levels of transcripts for CYP11A1, CYP11B1 and the other enzymes of corticosterone synthesis were detected in normal rat brain, in cerebral cortex and cerebellum [33], and 11 -hydroxylase protein expression was later demonstrated in the Purkinje cells and other cells of the hippocampus [35].…”