Pregnenolone Abstracts

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The following is a collection of pregnenolone Abstracts from published scientific research and papers. Integratedhealth.com offers Pregnenolone as a dietary supplement.

REFERENCE 1 OF 14

Khalsa DS

Integrated medicine and the prevention and reversal of memory loss.

In: Altern Ther Health Med (1998 Nov) 4(6):38-43

This article, based on scientific research and clinical observations, suggests that memory loss is not an inevitable consequence of aging and that Alzheimer’s disease can be prevented and reversed using an integrated medical approach. Three new associations with memory loss other than age, heredity, and genetics are described. They include a high-fat diet, chronic unbalanced stress with its attendant risk in the adrenal hormone cortisol, and the presence of cardiovascular disease. A 4-pillar integrative medical program on brain longevity is presented. The program includes a diet consisting of 15% fat and supplementation with brain-specific nutrients such as vitamin B complex, vitamin E, ubiquinone, ginkgo biloba, and phosphatidylserine. In addition, stress-relieving meditation, mind-body and cognitive exercise, antiaging drugs like L-deprenyl citrate, as well as hormones such as dehydroepiandrosterone and pregnenolone complete the program. Patient benefits such as greater wisdom and spiritual happiness are also explored.

Institutional address: Alzheimer’s Prevention Foundation, Tucson, Ariz., USA.

REFERENCE 2 OF 14

Semeniuk T, Jhangri GS, Le Melledo JM.

Neuroactive steroid levels in patients with generalized anxiety disorder.

J Neuropsychiatry Clin Neurosci 2001;13(3):396-398

Serum levels of allopregnanolone, pregnenolone sulfate, and dehydroepiandrosterone sulfate were measured in 8 male patients with generalized anxiety disorder (GAD) and 8 healthy control subjects. Results suggest that patients with GAD have significantly lower levels of pregnenolone sulfate than control subjects.

REFERENCE 3 OF 14

Schumacher M, Akwa Y, Guennoun R, Robert F, Labombarda F, Desarnaud F, Robel P, De Nicola AF, Baulieu EE

Steroid synthesis and metabolism in the nervous system: trophic and protective effects.

In: J Neurocytol (2000 May-Jun) 29(5-6):307-26

Steroids influence the activity and plasticity of neurons and glial cells during early development, and they continue to exert trophic and protective effects in the adult nervous system. Steroids are produced by the gonads and adrenal glands and reach the brain, the spinal cord and the peripheral nerves via the bloodstream. However, some of them, named “neurosteroids”, can also be synthesized within the nervous system. They include pregnenolone, progesterone, dehydroepiandrosterone and their reduced metabolites and sulfate esters. Little is known concerning the regulation of steroid synthesis in the nervous system, which involves interactions between different cell types. For example, the synthesis of progesterone by Schwann cells in peripheral nerves is regulated by a diffusible neuronal signal. Neurotrophic and neuroprotective effects of steroids have been documented both in cell culture and in vivo. PROG plays an important role in the neurological recovery from traumatic injury of the brain and spinal cord by mechanisms involving protection from excitotoxic cell death, lipid peroxydation and the induction of specific enzymes. After transection of the rat spinal cord, PROG increases the number of nitric oxide synthase expressing astrocytes immediately above and below the lesion. PROG also plays an important role in the formation of new myelin sheaths. This has been shown in the regenerating mouse sciatic nerve after lesion and in cocultures of sensory neurons and Schwann cells. PROG promotes myelination by activating the expression of genes coding for myelin proteins. The modulation of neurostransmitter receptors, in particular the type A gamma-aminobutyric acid, the N-methyl-D-aspartate and the sigma 1 receptors, is involved in the psychopharmacological effects of steroids and allows to explain their anticonvulsant, anxiolytic, antidepressive and sedative effects as well as their influence on memory. Pregnenolone sulfate has been shown to reverse age-related deficits in spatial memory performance and to have protective effects on memory in different models of amnesia.

Institutional address: U488 Inserm Kremlin-Bicetre France.

REFERENCE 4 OF 14

Rupprecht R

The neuropsychopharmacological potential of neuroactive steroids.

In: J Psychiatr Res (1997 May-Jun) 31(3):297-314

In addition to the well-known genomic effects of steroid molecules via intracellular steroid receptors, certain steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. The 3 alpha- hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been thought not to interact with intracellular receptors but enhance 7-aminobutyric acid (GABA)- mediated chloride currents, whereas pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate display functional antagonistic properties at GABAA receptors. We demonstrated that these neuroactive steroids can regulate also gene expression via the progesterone receptor after intracellular oxidation. Thus, in physiological concentrations these neuroactive steroids regulate neuronal function through their concurrent influence on transmitter-gated ion channels and gene expression. When administered in animal studies, memory enhancing effects have been shown for pregnenolone sulfate and DHEA. The 3 alpha-hydroxy ring A-reduced neuroactive steroids predominantly display anxiolytic, anticonvulsant and hypnotic activities. Sleep studies evaluating the effects of progesterone as a precursor molecule for these neuroactive steroids revealed a sleep EEG pattern similar to that obtained by the administration of benzodiazepines. These findings extend the concept of “cross-talk” between membrane and nuclear hormone effects and provide a new role for the therapeutic application of these steroids in neurology and psychiatry.

Institutional address: Max Planck Institute of Psychiatry Clinical Institute Munich Germany.

REFERENCE 5 OF 14

Mayo W, Le Moal M, Abrous DN.

Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations.

Horm Behav 2001 Sep;40(2):215-217

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently of peripheral sources. Several neurosteroids influence cognitive functions. Indeed, in senescent animals we have previously demonstrated a significant correlation between the cerebral concentration of pregnenolone sulfate (PREG-S) and cognitive performance. Indeed, rats with memory impairments exhibited low PREG-S concentrations compared to animals with correct memory performance. Furthermore, these memory deficits can be reversed by intracerebral infusions of PREG-S. Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, cortex, and hippocampus induced by central administrations of PREG-S. Central ACh neurotransmission is involved in the regulation of memory processes and is affected in normal aging and in human neurodegenerative pathologies like Alzheimer’s disease. ACh neurotransmission is also involved in the modulation of sleep-wakefulness cycle and relationships between paradoxical sleep and memory are well documented in the literature. PREG-S infused at the level of ACh cell bodies induces a dramatic increase of paradoxical sleep in young animals. Cognitive dysfunctions, particularly those observed in Alzheimer’s disease, have also been related to alterations of cerebral plasticity. Among these mechanisms, neurogenesis has been recently studied. Preliminary data suggest that PREG-S central infusions dramatically increase neurogenesis. Taken together these data suggest that PREG-S can influence cognitive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore our recent data suggest a role for neurosteroids in the modulation of hippocampal neurogenesis. Copyright 2001 Academic Press. PMID: 11534985 [PubMed – in process]

INSERM U259, Institut Francois Magendie, Rue Camille Saint-Saens, Bordeaux Cedex, 33077, France

REFERENCE 6 OF 14

Akwa Y, Baulieu EE

[Neurosteroids: behavioral aspects and physiological implications]

In: J Soc Biol (1999) 193(3):293-8

The term “neurosteroids” applies to those steroids that are both formed in the nervous system from sterol precursors, and accumulate in the nervous system, at least in part, independently of peripheral steroidogenic glands secretion. Neurosteroids that are active on the central nervous system include, mainly, pregnenolone (PREG), dehydroepiandrosterone (DHEA) and their sulfate esters (PREG-S and DHEA-S), as well as the reduced metabolite of progesterone, 3 alpha,5 alpha-TH PROG also called allopregnanolone. These neuroactive neurosteroids alter neuronal excitability by modulating the activity of several neurotransmitter receptors and thus can influence behavior. PREG-S decreases the sleeping time in rats anesthetized with a barbiturate, which is consistent with its antagonist action on the GABAA receptor (GABAA-R). Allopregnanolone is anxiolytic in rats tested in a conflict paradigm, through an interaction at a site specific for the benzodiazepine (BZ) receptor inverse agonist RO15- 4513 and/or at the picrotoxinin site on GABAA-R. The contribution of the amygdala, a key region involved in the control of anxiety, is also demonstrated for the anxiolytic action of allopregnanolone. An anti-agressive effect of DHEA can be observed in castrated male mice who become agressive in the presence of lactating females. This inhibition of agressiveness by DHEA is associated to a selective decrease in the brain of PREG-S, which may, in turn, trigger an increase of endogenous GABAergic tone. Finally, cognitive performances of aged rats tested in the Morris water maze and the Y- maze can be correlated with individual concentrations of PREG-S in the hippocampus, i.e. poor performance in both tasks with low levels of PREG-S. Remarkably, the memory deficits are significantly improved, albeit transiently, by an intra-hippocampal injection of PREG-S in impaired aged rats. Promnesiant PREG-S may then reinforce some neurotransmitter systems that can decline with age. This brief review provides evidence of the pharmacology and physiological correlates of neurosteroids involved in behavioral phenomena. However, neurobiological mechanisms of behavioral effects of neurosteroids await further investigation.

Institutional address: INSERM U488 Steroides et Systeme Nerveux Le Kremlin-Bicetre. yakwa@kb.inserm.

REFERENCE 7 OF 14

Tsutsui K, Ukena K, Usui M, Sakamoto H, Takase M

Novel brain function: biosynthesis and actions of neurosteroids in neurons.

In: Neurosci Res (2000 Apr) 36(4):261-73

Peripheral steroid hormones act on brain tissues through intracellular receptor-mediated mechanisms to regulate several important brain neuronal functions. Therefore, the brain is considered to be a target site of steroid hormones. However, it is now established that the brain itself also synthesizes steroids de novo from cholesterol. The pioneering discovery of Baulieu and his colleagues, using mammals, and our studies with non-mammals have opened the door of a new research field. Such steroids synthesized in the brain are called neurosteroids. Because certain structures in vertebrate brains have the capacity to produce neurosteroids, identification of neurosteroidogenic cells in the brain is essential to understand the physiological role of neurosteroids in brain functions. Glial cells are generally accepted to be the major site for neurosteroid formation, but the concept of neurosteroidogenesis in brain neurons has up to now been uncertain. We recently demonstrated neuronal neurosteroidogenesis in the brain and indicated that the Purkinje cell, a typical cerebellar neuron, actively synthesizes several neurosteroids de novo from cholesterol in both mammals and non-mammals. Pregnenolone sulfate, one of neurosteroids synthesized in the Purkinje neuron, may contribute to some important events in the cerebellum by modulating neurotransmission. Progesterone, produced as a neurosteroid in this neuron only during neonatal life, may be involved in the promotion of neuronal and glial growth and neuronal synaptic contact in the cerebellum. More recently, biosynthesis and actions of neurosteroids in pyramidal neurons of the hippocampus were also demonstrated. These serve an excellent model for the study of physiological roles of neurosteroids in the brain, because both cerebellar Purkinje neurons and hippocampal neurons play an important role in memory and learning. This paper summarizes the advances made in our understanding of neurosteroids, produced in neurons, and their actions.

Institutional address:Laboratory of Brain Science, Faculty of Integrated Arts and Sciences, Hiroshima University Higashi-Hiroshima Japan.

REFERENCE 8 OF 14

Pallares M, Darnaudery M, Day J, Le Moal M, Mayo W

The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory.

In: Neuroscience (1998 Dec) 87(3):551-8

The effects of an infusion (5 ng) of the neurosteroid pregnenolone sulfate into the nucleus basalis magnocellularis on acetylcholine release in the frontoparietal cortex and basolateral amygdala were evaluated during the 130 min post-injection in male Sprague-Dawley rats using in vivo microdialysis coupled “on line” with high performance liquid chromatography detection. One week later, the same animals were tested for spatial memory after another infusion of pregnenolone sulfate (5 ng) into the nucleus basalis. Results show that pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline concentrations in the two structures relative to a control injection. The duration of this effect was longer in cortex (130 min) than in amygdala (30 min). Furthermore, pregnenolone sulfate improved memory performance in a task based upon spatial recognition of a familiar environment. A significant positive correlation (r=0.49) was found between the recognition score in the spatial memory test and the levels of acetylcholine release in the frontoparietal cortex but not in the basolateral amygdala. Therefore, our results suggest that the nucleus basalis magnocellularis-cortical pathway could be in part responsible for the promnesic effect of pregnenolone sulfate. This neurosteroid acts as a negative modulator of the GABA(A) receptor complex and positively modulates the N-methyl- D-aspartate receptor, possibly resulting in a global stimulatory effect on central cholinergic neurotransmission.

Institutional address: Departament de Psicobiologia i Metodologia de les Ciencies de la Salut Facultat de Psicologia Universitat Autonoma de Barcelona Bellaterra Spain.

REFERENCE 9 OF 14

Vallee M, Mayo W, Darnaudery M, Corpechot C, Young J, Koehl M. Le Moal M, Baulieu EE, Robel P, Simon H

Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.

In: Proc Natl Acad Sci U S A (1997 Dec 23) 94(26):14865-70

Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22-24 month-old) male Sprague-Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a gamma-aminobutyric acid antagonist and a positive allosteric modulator at the N-methyl-D-aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and/or treatment of age-related memory disorders.

Institutional address: Laboratoire de Psychobiologie des Comportements Adaptatifs. Institut National de la Sante de la Recherche Medicale, Unite 259, rue Camille Saint Saens, 33077 Bordeaux cedex, France.

REFERENCE 10 OF 14

Flood JF, Morley JE, Roberts E

Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by far the most sensitive.

In: Proc Natl Acad Sci U S A (1995 Nov 7) 92(23):10806-10

Immediate post-training, stereotactically guided, intraparenchymal administration of pregnenolone sulfate (PS) into the amygdala, septum, mammillary bodies, or caudate nucleus and of PS, dehydroepiandrosterone sulfate, and corticosterone into the hippocampus was performed in mice that had been weakly trained in a foot-shock active avoidance paradigm. Intrahippocampal injection of PS resulted in memory enhancement (ME) at a lower dose than was found with dehydroepiandrosterone sulfate and corticosterone. Intraamygdally administered PS was approximately 10(4) times more potent on a molar basis in producing ME than when PS was injected into the hippocampus and approximately 10(5) times more potent than when injected into the septum or mammillary bodies. ME did not occur on injection of PS into the caudate nucleus over the range of doses tested in the other brain structures. The finding that fewer than 150 molecules of PS significantly enhanced post-training memory processes when injected into the amygdala establishes PS as the most potent memory enhancer yet reported and the amygdala as the most sensitive brain region for ME by any substance yet tested.

Institutional address: Geriatric Research Education and Clinical Center Veterans Administration Medical Center St. Louis MO 63106 USA.

REFERENCE 11 OF 14

Rupprecht R, Holsboer F

Neuropsychopharmacological properties of neuroactive steroids.

In: Steroids (1999 Jan-Feb) 64(1-2):83-91

In addition to the well-known genomic effects of steroid molecules via intracellular steroid receptors, certain steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. The 3alpha- hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been thought not to interact with intracellular receptors, but enhance gamma-aminobutyric acid (GABA)- mediated chloride currents, whereas pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate display functional antagonistic properties at GABA(A) receptors. We demonstrated that these neuroactive steroids can regulate also gene expression via the progesterone receptor after intracellular oxidation. Thus, in physiological concentrations these neuroactive steroids regulate neuronal function through their concurrent influence on transmitter- gated ion channels and gene expression. When administered in animal studies, memory-enhancing effects have been shown for pregnenolone sulfate and DHEA. The 3alpha-hydroxy ring A-reduced neuroactive steroids predominantly display anxiolytic, anticonvulsant, and hypnotic activities. Sleep studies evaluating the effects of progesterone as a precursor molecule for these neuroactive steroids revealed a sleep electroencephalogram pattern similar to that obtained by the administration of benzodiazepines. These findings extend the concept of a “cross-talk” between membrane and nuclear hormone effects and provide a new role for the therapeutic application of these steroids in neurology and psychiatry.

Institutional address: Department of Psychiatry, Ludwig Maximilian University, Munich, Germany.

REFERENCE 12 OF 14

Schumacher M, Guennoun R, Robel P, Baulieu EE

Neurosteroids in the Hippocampus: Neuronal Plasticity and Memory.

In: Stress (1997 Oct) 2(1):65-78

The hippocampus, which is critically involved in learning and memory processes, is known to be a target for the neuromodulatory actions of steroid hormones produced by the adrenal glands and gonads. Much of the work of B.S. McEwen and collaborators has focused on the role of glucocorticosteroids and estrogen in modulating hippocampal plasticity and functions. In addition to hormones derived from the endocrine glands, cells in the hippocampus may be exposed to locally synthesized neurosteroids, including pregnenolone, dehydroepiandrosterone and their sulfated esters as well as progesterone and its reduced metabolites. In contrast to hormones derived from the circulation, neurosteroids have paracrine and/or autocrine activities. In the hippocampus, they have been shown to have trophic effects on neurons and glial cells and to modulate the activity of a variety of neurotransmitter receptors and ion channels, including type A gamma-aminobutyric acid, N-methyl-D- aspartate and sigma receptors and N- and L-type Ca2+ channels. There is accumulating evidence that some neurosteroids, in particular pregnenolone sulfate, have strong influences on learning and memory processes, most likely by regulating neurotransmission in the hippocampus. However, the hippocampus is not the only target for the mnesic effects of neurosteroids. Associated brain regions, the basal nuclei of the forebrain and the amygdaloid complex, are also involved. Some neurosteroids may thus be beneficial for treating age- or disease- related cognitive impairments.

Institutional address: Lab. Hormones INSERM U33, 80 rue du General Leclerc, 94276 Bicetre, France.

REFERENCE 13 OF 14

Tagawa N, Tamanaka J, Fujinami A, Kobayashi Y, Takano T, Fukata S, Kuma K, Tada H, Amino N.

Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone sulfate concentrations in patients with hyperthyroidism and hypothyroidism.

Clin Chem 2000 Apr;46(4):523-528

BACKGROUND: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to have protective effects against cardiovascular disease, cancer, immune-modulated diseases, and aging. We examined serum concentrations of DHEA, DHEA-S, and pregnenolone sulfate (PREG-S) in patients with thyroid dysfunction. METHODS: Steroids extracted with methanol from serum sample were separated into an unconjugated fraction (DHEA) and a monosulfate fraction (DHEA-S and PREG-S), using a solid-phase extraction and an ion-exchange column. After separation of unconjugated steroids by HPLC, the DHEA concentration was measured by enzyme immunoassay. The monosulfate fraction was treated with arylsulfatase, and the freed steroids were separated by HPLC. The DHEA and PREG fractions were determined by gas chromatography-mass spectrometry, and the concentrations were converted into those of DHEA-S and PREG-S. RESULTS: Serum concentrations of DHEA, DHEA-S, and PREG-S were all significantly lower in patients with hypothyroidism (n = 24) than in age- and sex-matched healthy controls (n = 43). By contrast, in patients with hyperthyroidism (n = 22), serum DHEA-S and PREG-S concentrations were significantly higher, but the serum DHEA concentration was within the reference interval. Serum concentrations of these three steroids correlated with serum concentrations of thyroid hormones in these patients. Serum albumin and sex hormone-binding globulin concentrations were not related to these changes in the concentration of steroids. CONCLUSIONS: Serum concentrations of DHEA, DHEA-S, and PREG-S were decreased in hypothyroidism, whereas serum DHEA-S and PREG-S concentrations were increased but DHEA was normal in hyperthyroidism. Thyroid hormone may stimulate the synthesis of these steroids, and DHEA sulfotransferase might be increased in hyperthyroidism.

Clinical Chemistry Laboratory, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.t-noriko@kobe pharma-u.ac.jp

REFERENCE 14 OF 14

Mathis C, Meziane H, Ungerer A

[Models for the study of memory and neurosteroids]

In: J Soc Biol (1999) 193(3):299-306

The steroids dehydroepiandrosterone sulfate (DHEA-S) and pregnenolone sulfate (Preg-S) are naturally synthetized in the brain. They improve short term and long term memory performances in a variety of learning tasks and models of amnesia in rodents. DHEA-S and Preg-S modulate GABAergic and glutamatergic synaptic transmission through direct interactions with GABA-A, NMDA and/or sigma 1 membrane receptors. In addition, these two neurosteroids facilitate the release of acetylcholine and modulate synaptic plasticity phenomena in cerebral structures, such as the hippocampus, known to play a role in learning and memory processes. The possible links between these actions and the promnestic effects of DHEA-S and Preg-S are discussed in the present review.

Institutional address: Laboratoire d’Ethologie et de Neurobiologie URA 1295 CNRS Universite Louis Pasteur Strasbourg France