Neuroactive steroids: State of the art and new perspectives

Melcangi, Roberto Cosimo; García‐Segura, Luis M.; Mensah‐Nyagan, Ayikoe Guy

doi:10.1007/s00018-007-7403-5

Cited by 220 publications

(207 citation statements)

References 287 publications

(341 reference statements)

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“…Clearly, other factors must play a role in mediating age-related changes in white matter during male adolescence. These may include, for example, effects of testosterone metabolites such as dihydrotestosterone and 17-␤-estradiol acting, respectively, via androgen and estrogen receptors (Melcangi et al, 2008), or perhaps involve direct neural effects of gonadotropins, such as luteinizing hormone (Lei and Rao, 2001). Finally, future longitudinal studies will allow investigators to examine, in a more causal manner, whether or not there are any risks associated with fast vs slow growth of white matter during male adolescence vis-à-vis the individual's mental health.…”

Section: Discussionmentioning

confidence: 99%

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

et al. 2008

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The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n= 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath.

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Section: Discussionmentioning

confidence: 99%

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

et al. 2008

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“…The metabolism of PROG and testosterone has a deep impact on the mechanism of action of these neuroactive steroids. Indeed, while DHP, like PROG, is able to interact with the classical steroid receptor, the PROG receptor (PR; Melcangi et al 2008), THP is a potent ligand of a non-classical steroid receptor, such as the GABA-A receptor (Lambert et al 2003, Belelli & Lambert 2005. Similarly, DHT is able to interact with the androgen receptor (AR) while 3a-diol is a ligand of the GABA-A receptor .…”

Section: Neuroactive Steroids: State Of the Artmentioning

confidence: 99%

Neuroactive steroids, their metabolites, and neuroinflammation

Giatti¹,

Boraso²,

Melcangi³

et al. 2012

Journal of Molecular Endocrinology

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Neuroinflammation represents a common feature of many neurodegenerative diseases implicated both in their onset and progression. Neuroactive steroids act as physiological regulators and protective agents in the nervous system. Therefore, the attention of biomedical research has been recently addressed in evaluating whether neuroactive steroids, such as progestagens, androgens, and estrogens may also affect neuroinflammatory pathways. Observations so far obtained suggest a general anti-inflammatory effect with a beneficial relapse on several neurodegenerative experimental models, thus confirming the potentiality of a neuroprotective strategy based on neuroactive steroids. In this scenario, neuroactive steroid metabolism and the sophisticated machinery involved in their signaling are becoming especially attractive. In particular, because metabolism of neuroactive steroids as well as expression of their receptors is affected during the course of neurodegenerative events, a crucial role of progesterone and testosterone metabolites in modulating neuroinflammation and neurodegeneration may be proposed. In the present review, we will address this issue, providing evidence supporting the hypothesis that the efficacy of neuroactive steroids could be improved through the use of their metabolites.

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Rosati

Sturli

Cungi

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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a b s t r a c tNeurosteroids are involved in Central Nervous System development, brain functionality and neuroprotection but little is known about regulators of their biosynthesis. Recently gonadotropins, Gonadotropin-releasing Hormone (GnRH) and their receptors have been localized in different brain regions, such as hippocampus and cortex.Using human neuronal-like cells we found that GnRH up-regulates the expression of key genes of cholesterol and steroid synthesis when used in a narrow range around 1.0 nM. The expression of Hydroxysterol D24-reductase (seladin-1/DHCR24), that catalyzes the last step of cholesterol biosynthesis, is increased by 50% after 90 min of incubation with GnRH. StAR protein and P450 side chain cleavage (P450scc) are up-regulated by 3.3 times after 90 min and by 3.5 times after 3 h, respectively. GnRH action is mediated by LH and 1.0 nM GnRH enhances the expression of LH␤ as well.A two fold increase of cell cholesterol is induced after 90 min of GnRH incubation and 17␤-estradiol (E2) production is increased after 24, 48 and 72 h. These data indicate for the first time that GnRH regulates both cholesterol and steroid biosynthesis in human neuronal-like cells and suggest a new physiological role for GnRH in the brain.

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Neuroactive steroids: State of the art and new perspectives

Cited by 220 publications

References 287 publications

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

Growth of White Matter in the Adolescent Brain: Role of Testosterone and Androgen Receptor

Neuroactive steroids, their metabolites, and neuroinflammation

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

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