Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates

Röbel, P; Young, Jacques; Corpéchot, C.; Mayo, Willy; Perché, Fabrice; Haug, Marc; Simon, H.; Baulieu, Étienne Émile

doi:10.1016/0960-0760(95)00074-a

Cited by 104 publications

(38 citation statements)

References 10 publications

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“…The enzymatic activity of Cyp11a1 was assessed using an ELISA for detection of pregnenolone levels in cell culture supernatants (21). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jia

Domenico

Takeda

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Allergic asthma is a heterogeneous inflammatory disorder of the airways characterized by chronic airway inflammation and airway hyperresponsiveness. Numbers of CD8 + IL-13 + T cells are increased in asthmatics and during the development of experimental asthma in mice. In an atopic environment rich in IL-4, these CD8 + T cells mediate asthmatic responses, but the mechanisms regulating the conversion of CD8 + effector T cells from IFN-γ– to pathogenic IL-13–producing effector cells that contribute to an asthma phenotype have not been defined. Here, we show that cholesterol side-chain cleavage P450 enzyme, Cyp11a1, is a key regulator of CD8 + T-cell conversion. Expression of the gene, protein, and enzymatic activity of Cyp11a1 were markedly increased in CD8 + T cells differentiated in the presence of IL-2 plus IL-4 compared with cells differentiated in IL-2 alone. Inhibition of Cyp11a1 enzymatic activity with aminoglutethimide or reduction in the expression of Cyp11a1 using short hairpin RNA prevented the IL-4–induced conversion of IFN-γ– to IL-13–producing cells without affecting expression of the lineage-specific transcription factors T-box expressed in T cells (T-bet) or GATA binding protein 3 (GATA3). Adoptive transfer of aminoglutethimide-treated CD8 + T cells into sensitized and challenged CD8-deficient recipients failed to restore airway hyperresponsiveness and inflammation. We demonstrate that Cyp11a1 controls the phenotypic conversion of CD8 + T cells from IFN-γ to IL-13 production, linking steroidogenesis in CD8 + T cells, a nonclassical steroidogenic tissue, to a proallergic differentiation pathway.

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“…The enzymatic activity of Cyp11a1 was assessed using an ELISA for detection of pregnenolone levels in cell culture supernatants (21). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Jia

Domenico

Takeda

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Peripherally administered 5␣-DHP, the immediate precursor of ALLO (see Fig. 1), and PROG accumulate in the brain; both steroids can be converted into ALLO in the brain (17,22). However, the rates of the conversion of PROG to 5␣-DHP and 5␣-DHP to ALLO in the brain depend on the kinetic properties of the pertinent enzymes: PROG is converted to 5␣-DHP by the action of type 1 (the most abundant isoform in brain) or type 2 5␣-reductase (Fig.…”

Section: Discussionmentioning

confidence: 99%

Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine

Uzunova

Sheline

Davis³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

622

446

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We recently reported that f luoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3␣-hydroxy-5␣-pregnane-20-one (3␣5␣-ALLO) without altering the brain content of other neurosteroids. ALLO (3␣5␣ and 3␣5␤ isomers) binds with high affinity to various ␥-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal f luid (CSF) before and 8-10 weeks after treatment with f luoxetine or f luvoxamine in 15 patients with unipolar major depression. The concentration of ALLO (Ϸ40 fmol͞ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, f luoxetine or f luvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r ‫؍‬ 0.58; P < 0.023; n ‫؍‬ 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after f luoxetine or f luvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of f luoxetine or f luvoxamine via its positive allosteric modulation of GABA type A receptors.Fluoxetine, fluvoxamine, and other selective 5HT reuptake inhibitors (SSRIs) have a spectrum of therapeutic actions that is broader than that of the monoamine oxidase inhibitors or the tricyclic imipramine-like antidepressants (1-5). Because several lines of evidence indicate that the action of various antidepressant classes is related to an enhancement of serotonin (5HT)-mediated neurotransmission and SSRIs are more selective in inhibiting 5HT reuptake than tricyclic antidepressants (6), it is possible that the therapeutic properties that are exclusively elicited by SSRIs may not depend only on 5HT neurotransmission for their action.We have recently reported that fluoxetine and paroxetine, two SSRIs, but not imipramine, when administered to rats, increase the steady-state brain content of the neurosteroid 3␣-hydroxy-5␣-pregnane-20-one (3␣5␣-ALLO), without altering the brain content of other neurosteroids (7) (for chemical structure and biosynthetic pathways of neurosteroids, see Fig.

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“…Given exogenously, they are anxyiolytic, anticonvulsant compounds. The neurosteroid pregnenolone has been shown to enhance memory when given intrathecally (Flood, et al, 1992,Flood, et al, 1995,Mathis, et al, 1994,Mayo, et al, 1993,Robel, et al, 1995. In rodent models of alcohol intoxication, one mechanism through which alcohol elicits its effects is through increased synthesis of allopregnanolone in the brain (Brot, et al, 1997,Caldeira, et al, 2004,Finn, et al, 2004,Finn, et al, 2003,Follesa, et al, 2004,Grobin, et al, 2005,Janis, et al, 1998,VanDoren, et al, 2000.…”

Section: Introductionmentioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates

Cited by 104 publications

References 10 publications

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

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Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates

Cited by 104 publications

References 10 publications

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+T cell skewing in allergic lung disease

Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

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Product

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Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease

Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8⁺T cell skewing in allergic lung disease