Neurosteroids: Biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain

Akwa, Yvette; Young, Jacques; Kabbadj, Khadija; Sancho, María J.; Zucman, David; Vourc’h, Claire; Jung-Testas, Ingrid; Hu, Zhong Yi; Goascogne, C. Le; Jo, D; Corpéchot, C.; Simon, Patricia; Baulieu, Étienne Émile; Röbel, P

doi:10.1016/0960-0760(91)90169-6

Cited by 158 publications

(73 citation statements)

References 43 publications

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“…P450scc is strongly expressed in the white (34), and neuronal expression of P450scc is generally lower than that of glia (13)(14)(15)(16). Interestingly, the cerebellar Purkinje cell possesses this steroidogenic enzyme and produces neurosteroids de novo in a number of vertebrates, including mammalian species (20,35,36), particularly fetal and neonatal sheep (20).…”

Section: Discussionmentioning

confidence: 99%

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Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep

et al. 2003

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Pregnane steroids have sedative and neuroprotective effects on the brain as a result of interactions with the steroid-binding site of the GABA A receptor. To determine whether the fetal brain is able to synthesize pregnane steroids de novo from cholesterol, we measured the expression of cytochrome P450 side-chain cleavage (P450scc) and 5␣-reductase type II (5␣RII) enzymes in fetal sheep from 72 to 144 d gestation (term~147 d) and in newborn lambs at 3 and 19-26 d of age. Both P450scc and 5␣RII expression was detectable by 90 d gestation in the major regions of the brain and also in the adrenal glands. Expression increased with advancing gestation and was either maintained at fetal levels or increased further after birth. In contrast, the relatively high content (200-400 pmol/g) of allopregnanolone (5␣-pregnan-3␣-ol-20-one), a major sedative 5␣-pregnane steroid, present throughout the brain from 90 d gestation to term, was reduced significantly (Ͻ50 pmol/g) immediately after birth. These results suggest that although the perinatal brain has the enzymes potentially to synthesize pregnane steroids de novo from cholesterol, either the placenta is a major source of these steroids to the brain or other factors associated with intrauterine life may be responsible for high levels of allopregnanolone production in the fetal brain until birth. Abbreviations AP, allopregnanolone, 5␣-pregnan-3␣-ol-20-one P450scc, P450 side chain cleavage enzyme 5␣RII, 5␣-reductase type II enzyme PMC, primary motor cortex GABA A ,␥-aminobutyric acid/benzodiazepine receptor 5␣-DHP, 5␣-dihydroprogesterone Neuroactive steroids such as allopregnanolone (AP) are potent neuromodulators that modify the excitability of the CNS by interaction with the ␥-aminobutyric acid/benzodiazepine receptor-chloride ionophore (GABA A receptor). In the adult AP is a positive allosteric modulator of the GABA A receptor with potent anxiolytic (1, 2), anticonvulsant (3, 4), sedative/ hypnotic, and anesthetic effects (5) on behavior. Prenatally, neuroactive steroids have been shown to suppress fetal activity in late gestation and seem to have a role in maintaining the low level of arousal-like behavior that typifies fetal life (6, 7). This interaction between AP and the GABA A receptor complex is responsible for the major pharmacologic actions of AP and is distinct from the genomic effects exerted by other steroids such as progesterone (8). In the brain, neuroactive steroids such as AP are synthesized de novo from cholesterol, but a proportion of the pool of steroids may be derived from precursors in blood that enter the brain across the blood-brain barrier (9 -11). Thus, peripheral steroidogenesis may influence neuroactive steroid content in the brain.The cytochrome P450 side-chain cleavage enzyme (P450scc) catalyzes the irreversible conversion of cholesterol to pregnenolone on the inner side of the mitochondrial membrane (12). The primary site of pregnenolone synthesis in the brain seems to be in oligodendrocytes and astrocytes, with significantly less synthesis occ...

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Section: Discussionmentioning

confidence: 99%

“…The primary site of pregnenolone synthesis in the brain seems to be in oligodendrocytes and astrocytes, with significantly less synthesis occurring in neurons (13)(14)(15)(16). 5␣-reductase catalyzes the irreversible conversion of progesterone to 5␣-dihydroprogesterone (5␣-DHP), the immediate precursor for AP formation.…”

mentioning

confidence: 99%

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep

et al. 2003

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“…The animals were housed in a temperature-controlled room (8 Ϯ 0.5°C) under running water, on a 12 h light/dark schedule (lights on from 6:00 A.M. to 6:00 P.M.), for at least 1 week before use. To limit possible variations of neurosteroid biosynthesis attributable to circadian rhythms (Akwa et al, 1991) (Tremblay et al, 1994) as well as a monoclonal antibody against VP (Robert et al, 1985) were used as primary antibodies for immunohistochemistry. Alexa 594-conjugated goat anti-rabbit ␥-globulins (GARs/Alexa 594) and Alexa 488-conjugated goat anti-mouse ␥-globulins (GAMs/Alexa 488), both from Invitrogen (Carlsbad, CA), were used as secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

Vasotocin and Mesotocin Stimulate the Biosynthesis of Neurosteroids in the Frog Brain

do-Rego

Acharjee

Seong

et al. 2006

Journal of Neuroscience

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The stimulatory effect of VT and MT on neurosteroid biosynthesis was mimicked by VP and OT, as well as by a selective V1b receptor agonist, whereas V2 and OT receptor agonists had no effect. VT-induced neurosteroid production was completely suppressed by selective V1a receptor antagonists and was not affected by V2 and OT receptor antagonists. Concurrently, the effect of MT on neurosteroidogenesis was markedly attenuated by selective OT and V1a receptor antagonists but not by a V2 antagonist. The present study provides the first evidence for a regulatory effect of VT and MT on neurosteroid biosynthesis. These data suggest that neurosteroids may mediate some of the behavioral actions of VT and MT.

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“…Little is known about GABA receptor subunit specificity of pregnenolone sulfate. However, similar to picrotoxin, it antagonizes the GABA mediated Cl current, but at a different binding site (Majewska & Schwartz 1987, Akwa et al 1991, Shen et al 1999. Mutation to the 2 subunit, eliminating picrotoxin sensitivity, does not block the antagonistic properties of pregnenolone sulfate (Shen et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Acute neurosteroid modulation and subunit isolation of the gamma-aminobutyric acidA receptor in the bullfrog, Rana catesbeiana

Hollis

Goetz²,

Roberts³

et al. 2004

Journal of Molecular Endocrinology

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The inhibitory neurotransmitter -aminobutyric acid (GABA) has multiple receptors. In mammals, the GABA A receptor subtype is modulated by neurosteroids. However, whether steroid interaction with the GABA A receptor is unique to mammals or a conserved feature in vertebrates is unknown. Thus, neurosteroid modulation of the GABA A receptor was investigated in the brain of the bullfrog (Rana catesbeiana) using the mammalian GABA A receptor agonist [ 3 H]muscimol. Two neurosteroids, allopregnanolone and pregnenolone sulfate, affected [ 3 H]muscimol specific binding in bullfrog brain membrane preparations. Allopregnanolone significantly increased [ 3 H]muscimol specific binding in a dose-and time-dependent manner. The pattern of allopregnanolone modulation supports the hypothesis that the bullfrog brain possesses both high-affinity and low-affinity [ 3 H]muscimol binding sites. Unlike allopregnanolone, pregnenolone sulfate showed biphasic modulation with increased [ 3 H]muscimol specific binding at low nanomolar concentrations and decreased specific binding at micromolar concentrations. Additionally, three cDNA fragments with significant homology to mammalian GABA A receptor subunits were isolated from the bullfrog brain. These fragments belong to the 1, 1, and 2 subunit families. In mammals, GABA A receptors composed of these specific subunit isoforms are effectively modulated by neurosteroids, including allopregnanolone. Neurosteroid modulation of the amphibian brain GABA A receptor is therefore supported by both [ 3 H]muscimol binding studies and subunit sequences. Allopregnanolone and pregnenolone sulfate modulation of this receptor may thus represent a significant mechanism for steroid influence on amphibian brain and behavior.

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Neurosteroids: Biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain

Cited by 158 publications

References 43 publications

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep

Vasotocin and Mesotocin Stimulate the Biosynthesis of Neurosteroids in the Frog Brain

Acute neurosteroid modulation and subunit isolation of the gamma-aminobutyric acidA receptor in the bullfrog, Rana catesbeiana

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