Neurosteroid biosynthesis in vertebrate brains

Tsutsui, Kazuyoshi; Ukena, Kazuyoshi; Takase, Miyuki; Kohchi, Chie; Lea, Robert

doi:10.1016/s0742-8413(99)00065-1

Cited by 96 publications

(107 citation statements)

References 70 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). This is consistent with the high level of cerebellar P450scc expression found in the present study.…”

Section: Discussionsupporting

confidence: 90%

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: Discussionsupporting

confidence: 90%

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

et al. 2003

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“…In contrast, new findings over the past decade have shown that the brain itself also has the capability of forming steroids de novo, the so-called "neurosteroids." Studies on mammals (for review, see Baulieu, 1997;Compagnone and Mellon, 2000) and nonmammals (for review, see Tsutsui et al, 1999Tsutsui et al, , 2003Mellon and Vaudry, 2001) indicate that de novo neurosteroidogenesis in the brain from cholesterol is a conserved property of vertebrates. Our studies using Japanese quail have demonstrated that the avian brain possesses the key steroidogenic enzyme, cytochrome P450 side-chain cleavage enzyme (P450scc) (CYP11A), and produces pregnenolone, a precursor of neurosteroids Usui et al, 1995;Tsutsui et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

7α-Hydroxypregnenolone Mediates Melatonin Action Underlying Diurnal Locomotor Rhythms

Tsutsui¹,

et al. 2008

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Melatonin regulates diurnal changes in locomotor activity in vertebrates, but the molecular mechanism for this neurohormonal regulation of behavior is poorly understood. Here we show that 7␣-hydroxypregnenolone, a previously undescribed avian neurosteroid, mediates melatonin action on diurnal locomotor rhythms in quail. In this study, we first identified 7␣-hydroxypregnenolone and its stereoisomer 7␤-hydroxypregnenolone in quail brain. These neurosteroids have not been described previously in avian brain. We then demonstrated that 7␣-hydroxypregnenolone acutely increased quail locomotor activity. To analyze the production of 7␣-hydroxypregnenolone, cytochrome P450 7␣ , a steroidogenic enzyme of this neurosteroid, was also identified. Subsequently, we demonstrated diurnal changes in 7␣-hydroxypregnenolone synthesis in quail. 7␣-Hydroxypregnenolone synthesis and locomotor activity in males were much higher than in females. This is the first demonstration in any vertebrate of a clear sex difference in neurosteroid synthesis. This sex difference in 7␣-hydroxypregnenolone synthesis corresponded to the sex difference in locomotion. We show that only males exhibited marked diurnal changes in 7␣-hydroxypregnenolone synthesis, and these changes occurred in parallel with changes in locomotor activity. Finally, we identified melatonin as a key component of the mechanism regulating 7␣-hydroxypregnenolone synthesis. Increased synthesis of 7␣-hydroxypregnenolone occurred in males in vivo after melatonin removal via pinealectomy and orbital enucleation (Px plus Ex). Conversely, decreased synthesis of this neurosteroid occurred after melatonin administration to Px plus Ex males. This study demonstrates that melatonin regulates synthesis of 7␣-hydroxypregnenolone, a key factor for induction of locomotor activity, thus inducing diurnal locomotor changes in male birds. This is a previously undescribed role for melatonin.

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“…[1][2][3] and nonmammals (for reviews, see refs. [3][4][5][6] indicate that de novo neurosteroidogenesis in the brain from cholesterol is a conserved property of vertebrates.…”

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7α-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system

Morikura

Ukena

Baulieu

et al. 2004

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

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192

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It is becoming clear that steroids can be synthesized de novo by the brain and other nervous systems. Such steroids are called neurosteroids, and de novo neurosteroidogenesis from cholesterol is a conserved property of vertebrate brains. In this study, we show that the newt brain actively produces 7␣-hydroxypregnenolone, a previously undescribed amphibian neurosteroid that stimulates locomotor activity. 7␣-hydroxypregnenolone was identified as a most abundant amphibian neurosteroid in the newt brain by using biochemical techniques combined with HPLC, TLC, and GC-MS analyses. The production of 7␣-hydroxypregnenolone in the diencephalon and rhombencephalon was higher than that in the telencephalon and peripheral steroidogenic glands. In addition, 7␣-hydroxypregnenolone synthesis in the brain showed marked changes during the annual breeding cycle, with a maximal level in the spring breeding period when locomotor activity of the newt increases. Behavioral analysis of newts in the nonbreeding period demonstrated that administration of this previously undescribed amphibian neurosteroid acutely increased locomotor activity. In vitro analysis further revealed that 7␣-hydroxypregnenolone treatment resulted in a dose-dependent increase in the release of dopamine from cultured brain tissue of nonbreeding newts. The effect of this neurosteroid on locomotion also was abolished by dopamine D 2-like receptor antagonists. These results indicate that 7␣-hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts through the dopaminergic system. This study demonstrates a physiological function of 7␣-hydroxypregnenolone that has not been described previously in any vertebrate class. This study also provides findings on the regulatory mechanism of locomotor activity from a unique standpoint.neurosteroids ͉ dopamine release ͉ newt brain ͉ seasonal changes

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Neurosteroid biosynthesis in vertebrate brains

Cited by 96 publications

References 70 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

7α-Hydroxypregnenolone Mediates Melatonin Action Underlying Diurnal Locomotor Rhythms

7α-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system

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