Distribution of 3α-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans

Khanna, Marilyn; Qin, Kenan; Cheng, K.-C.

doi:10.1016/0960-0760(95)00019-v

Cited by 40 publications

(16 citation statements)

References 24 publications

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“…Both enzymes are nonuniformly distributed in the brain; the highest content of these enzymes (27,30) and of 5a-DH PROG and 3a,5a-TH PROG (see Table 1) is found in the olfactory bulb. Thus, the nonuniform increase in brain 3a,5a-TH PROG following fluoxetine (Table 1), which in ADX/CX rats occurs without concomitant changes of PREG or PROG content (Fig.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.

Uzunov

Cooper

Costa

et al. 1996

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

314

219

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Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 ,umol/kg i.p.) increased the brain content of the neurosteroid 3c-hydroxy-5a-pregnan-20-one (allopregnanolone, 3a,5a-TH PROG). The increase of brain 3a,5a-TH PROG content elicited by 58,umol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated (--3-10 pmol/g) and ADX/CX rats (2-9 pmol/g) and was associated with a decrease (from 2.8 to 1.1 pmol/g) in the 5a-pregnan-3,20-dione (5a-dihydroprogesterone, 5a-DH PROG) content. The pregnenolone, progesterone, and dehydroepiandrosterone content failed to change in rats receiving fluoxetine. The extent of 3a,5a-TH PROG accumulation elicited by fluoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb. Importantly, fluoxetine failed to change the 3a,5ca-TH PROG levels in plasma, which in ADX/CX rats were at least two orders of magnitude lower than in the brain. Two other serotonin re-uptake inhibitors, paroxetine and imipramine, in doses equipotent to those of fluoxetine in inhibiting brain serotonin uptake, were either significantly less potent than fluoxetine (paroxetine) or failed to increase (imipramine) 3a,5ci-TH PROG brain content. The addition of 10 ,uM of 5a-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 IuM, 15 min) elicited an accumulation of 3a,5a-TH PROG greater than in slices preincubated with vehicle. A fluoxetine stimulation of brain 3a,5ai-TH PROG biosynthesis might be operative in the anxiolytic and antidysphoric actions of this drug.Neurosteroids such as 3a-hydroxy-5a-pregnan-20-one (allopregnanolone, 3a,5a-TH PROG); pregnenolone (PREG) sulfate; and dehydroepiandrosterone (DHEA), sulfate, promptly decrease or increase brain excitability acting as potent positive (3a,5a-TH PROG) or negative (PREG sulfate, DHEA sulfate) allosteric modulators of y-aminobutyric acid (GABA) action at GABAA receptors (1-6). These discoveries have provided a new mechanism for brain GABAergic tone modification applicable to the treatment of various neuropsychiatric disorder symptoms (7,8). These include the anxiety and mood changes of the "late luteal dysphoria syndrome," associated with low progesterone (PROG) plasma levels (a steroid participating in 3a,5a-TH PROG biosynthesis) (8, 9).Though the prospect that neuroactive steroids could be used in the symptomatic treatment of specific neurological and psychiatric disorders has generated some enthusiasm, substantial difficulties prevent the therapeutic use of neurosteroids. For example, the systemic administration of 3a,5a reduced derivatives of PROG or androstenedione acting as positive allosteric modulators of GABA action at GABAA receptors, indicates that the doses required to elicit a clear anxiolytic, antidysphoric, and antiepileptic activity may also produce profound sedation, motor impairment, or ataxia (6,8,10). Two additional pharmacological actions that may li...

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Section: Discussionmentioning

confidence: 99%

Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.

Uzunov

Cooper

Costa

et al. 1996

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

314

219

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“…Enzymes responsible for synthesis of 3␣-OH-DHP from progesterone, 5␣-reductase and 3␣-OH steroid oxidoreductase, are present in the medulla (105,118,168), and ovarian hormones can regulate 3␣-OH-DHP synthesis in brain tissue (131). Importantly, differences in peripheral and CNS levels of 3␣-OH-DHP during pregnancy suggest that local regulation determines the effective concentrations of 3␣-OH-DHP in a brain region-specific manner (14,38,168,173).…”

Section: Neurosteroid Metabolite Of Progesterone: a Contributor To Atmentioning

confidence: 99%

Pregnancy and the endocrine regulation of the baroreceptor reflex

Brooks

Dampney

Heesch

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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-The purpose of this review is to delineate the general features of endocrine regulation of the baroreceptor reflex, as well as specific contributions during pregnancy. In contrast to the programmed changes in baroreflex function that occur in situations initiated by central command (e.g., exercise or stress), the complex endocrine milieu often associated with physiological and pathophysiological states can influence the central baroreflex neuronal circuitry via multiple sites and mechanisms, thereby producing varied changes in baroreflex function. During pregnancy, baroreflex gain is markedly attenuated, and at least two hormonal mechanisms contribute, each at different brain sites: increased levels of the neurosteroid 3␣-hydroxydihydroprogesterone (3␣-OH-DHP), acting in the rostral ventrolateral medulla (RVLM), and reduced actions of insulin in the forebrain. 3␣-OH-DHP appears to potentiate baroreflex-independent GABAergic inhibition of premotor neurons in the RVLM, which decreases the range of sympathetic nerve activity that can be elicited by changes in arterial pressure. In contrast, reductions in the levels or actions of insulin in the brain blunt baroreflex efferent responses to increments or decrements in arterial pressure. Although plasma levels of angiotensin II are increased in pregnancy, this is not responsible for the reduction in baroreflex gain, although it may contribute to the increased level of sympathetic nerve activity in this condition. How these different hormonal effects are integrated within the brain, as well as possible interactions with additional potential neuromodulators that influence baroreflex function during pregnancy and other physiological and pathophysiological states, remains to be clearly delineated.3␣-hydroxy-dihydroprogesterone; angiotensin II; insulin; paraventricular nucleus of the hypothalamus NORMAL PREGNANCY is characterized by profound changes in fluid and electrolyte balance and blood pressure regulation. Blood volume and cardiac output increase by 30 -50%, but arterial pressure falls due to even greater decreases in systemic vascular resistance (120,138,189). These hemodynamic alterations are evident early in pregnancy, precede the increases in uterine blood flow, and are sustained until parturition (127,138,189). Considerable data implicate increases in relaxin and nitric oxide (NO) in the systemic vasodilation induced by pregnancy (20,127,128,177,196). In addition, peripheral vascular sensitivity to circulating vasoconstrictors including vasopressin, angiotensin II (ANG II), and norepinephrine (NE) is decreased (50,71,154).Unlike the hemodynamic changes, which likely subserve adequate fetal development, an adverse consequence of normal pregnancy is a marked impairment of the arterial baroreceptor reflex. This change was first noted by Humphreys and Joels (97,98) in an extensive series of studies in anesthetized pregnant rabbits, in which reductions in carotid sinus pressure failed to elicit normal increases in arterial pressure and peripheral vascular resistanc...

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“…The spinal cord (SC) received little attention, although this part of the CNS is crucial for many neurophysiological mechanisms, including somatosensory transmission, nociception, locomotion, spinal reflex, and neurovegetative functions (for review see Haines et al, 1997). 3␣-HSD activity was detected in the olfactory bulb, but immunocytochemical localization of the enzyme has never been determined in the CNS Scott, 1984, 1989;Khanna et al, 1995). The 3␣-HSD purified from rat brain cytosol exhibited the same molecular weight and inhibitory properties as the rat liver enzyme (Penning et al, 1985).…”

mentioning

confidence: 99%

Anatomical and cellular localization of neuroactive 5α/3α‐reduced steroid‐synthesizing enzymes in the spinal cord

Patte‐Mensah

Penning

Mensah‐Nyagan

2004

J of Comparative Neurology

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The complementary activities of 5 alpha-reductase (5 alpha-R) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) are crucial for the synthesis of neuroactive 5 alpha/3 alpha-reduced steroids, such as 3 alpha-androstanediol, allopregnanolone, and tetrahydrodeoxycorticosterone, which control several important neurophysiological mechanisms through allosteric modulation of gamma-aminobutyric acid type A receptors. Immunocytochemical localization of 3 alpha-HSD in the central nervous system (CNS) has never been determined. The presence and activity of 5 alpha-R have been investigated in the CNS, but only the brain was considered; the spinal cord (SC) received little attention, although this structure is crucial for many sensorimotor activities. We have determined the first cellular distribution of 5 alpha-reductase type 1 (5 alpha-R1) and type 2 (5 alpha-R2) and 3 alpha-HSD immunoreactivities in adult rat SC. 5 alpha-R1 immunostaining was detected mainly in the white matter (Wm). In contrast, intense 5 alpha-R2 labeling was observed in dorsal (DH) and ventral horns of gray matter (Gm). 3 alpha-HSD immunoreactivity was largely distributed in the Wm and Gm, but the highest density was found in sensory areas of the DH. Double-labeling experiments combined with confocal analysis revealed that, in the Wm, 5 alpha-R1 was localized in glial cells, whereas 35% of 5 alpha-R2 and 3 alpha-HSD immunoreactivities were found in neurons. In the DH, 60% of 5 alpha-R2 immunostaining colocalized with oligodendrocyte, 25% with neuron, and 15% with astrocyte markers. Similarly, 45% of 3 alpha-HSD immunoreactivity was found in oligodendrocytes, 35% in neurons, and 20% in astrocytes. These results are the first demonstrating that oligodendrocytes and neurons of the SC possess the key enzymatic complex for synthesizing potent neuroactive steroids that may control spinal sensorimotor processes.

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Distribution of 3α-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans

Cited by 40 publications

References 24 publications

Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.

Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.

Pregnancy and the endocrine regulation of the baroreceptor reflex

Anatomical and cellular localization of neuroactive 5α/3α‐reduced steroid‐synthesizing enzymes in the spinal cord

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