Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565-575

Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee University, Dundee DD19SY, UK.
Nature reviews Neuroscience (Impact Factor: 31.43). 08/2005; 6(7):565-75. DOI: 10.1038/nrn1703
Source: PubMed


GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

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    • "Accordingly, ALLO can play a dual role in the nervous system. First, like progesterone (via classical steroid receptors) from which it is derived, ALLO can exert a protective and regenerative role on the brain and the spinal cord ([37] for review, [41] [42] [43] [44] [45]). "
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    ABSTRACT: Impaired biosynthesis of Allopregnanolone (ALLO), a brain endogenous neurosteroid, has been associated with numerous behavioral dysfunctions, which range from anxiety- and depressive-like behaviors to aggressive behavior and changes in responses to contextual fear conditioning in rodent models of emotional dysfunction. Recent animal research also demonstrates a critical role of ALLO in social isolation. Although there are likely aspects of perceived social isolation that are uniquely human, there is also continuity across species. Both human and animal research show that perceived social isolation (which can be defined behaviorally in animals and humans) has detrimental effects on physical health, such as increased hypothalamic pituitary adrenal (HPA) activity, decreased brain-derived neurotrophic factor (BDNF) expression, and increased depressive behavior. The similarities between animal and human research suggest that perceived social isolation (loneliness) may also be associated with a reduction in the synthesis of ALLO, potentially by reducing BDNF regulation and increasing HPA activity through the hippocampus, amygdala, and bed nucleus of the stria terminalis (BNST), especially during social threat processing. Accordingly, exogenous administration of ALLO (or ALLO precursor, such as pregnenolone), in humans may help alleviate loneliness. Congruent with our hypothesis, exogenous administration of ALLO (or ALLO precursors) in humans has been shown to improve various stress-related disorders that show similarities between animals and humans i.e., post-traumatic stress disorders, traumatic brain injuries. Because a growing body of evidence demonstrates the benefits of ALLO in socially isolated animals, we believe our ALLO hypothesis can be applied to loneliness in humans, as well.
    Medical Hypotheses 09/2015; DOI:10.1016/j.mehy.2015.09.004 · 1.07 Impact Factor
    • "GABAergic tone is also modulated by neurosteroids. Some neurosteroids (allopregnanolone, tetrahydrodeoxy-corticosterone: THDOC; 5alpha-androstane-3alpha-17betadiol; pregnanolone) enhance and others (dehydroepiandrosterone: DHEA; DHEA sulfate ester and pregnenolone sulfate) reduce GABAA receptors activation (Majewska et al., 1986; 1988; 1990; Ermirio et al., 1989; Paul and Purdy, 1992; Barbaccia et al., 2000; Belelli and Lambert, 2005). The effects of some neurosteroids depend on the subunit composition of GABAA receptors. "
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    ABSTRACT: Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome affecting patients with liver diseases, mainly those with liver cirrhosis. The mildest form of HE is minimal HE (MHE), with mild cognitive impairment, attention deficit, psychomotor slowing and impaired visuo-motor and bimanual coordination. MHE may progress to clinical HE with worsening of the neurological alterations which may lead to reduced consciousness and, in the worse cases, may progress to coma and death. HE affects several million people in the world and is a serious health, social and economic problem. There are no specific treatments for the neurological alterations in HE. The mechanisms underlying the cognitive and motor alterations in HE are beginning to be clarified in animal models. These studies have allowed to design and test in animal models of HE new therapeutic approaches which have successfully restored cognitive and motor function in rats with HE. In this article we review the evidences showing that. Copyright © 2015. Published by Elsevier Ltd.
    The Journal of steroid biochemistry and molecular biology 08/2015; DOI:10.1016/j.jsbmb.2015.08.020 · 3.63 Impact Factor
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    • "5a-reductase inhibition by blocking the metabolism of T and P to its metabolites, could lead to accumulation of precursors and some of them have shown neuroprotective activity in MPTP mice such as estrogens, P and dehydroepiandrosterone (DHEA) (Bourque et al., 2009) (Callier et al., 2001). Given that the P metabolite AP also exhibits protective activity in MPTP mice (Adeosun et al., 2012), neuroprotective effects could be due to activation of P receptor by P and DHP, and also to activation of the g-aminobutyric acid type A (GABA-A) receptor by AP (Belelli and Lambert, 2005). The neuroprotective effects observed here are not likely to be mediated by GABA-A activation by AP since this metabolite is likely decreased due to reduction of P metabolism by 5a-reductase inhibition. "
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    ABSTRACT: Finasteride and Dutasteride are 5α-reductase inhibitors used in the clinic to treat endocrine conditions and were recently found to modulate brain dopamine (DA) neurotransmission and motor behaviour. We investigated if Finasteride and Dutasteride have a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice as a model of Parkinson's disease (PD). Experimental groups included saline treated controls and mice treated with saline, Finasteride (5 and 12.5 mg/kg) or Dutasteride (5 and 12.5 mg/kg) for 5 days before and 5 days after MPTP administration (4 MPTP injections, 6.5 mg/kg on day 5 inducing a moderate DA depletion) and then they were euthanized. MPTP administration decreased striatal DA contents measured by HPLC while serotonin contents remained unchanged. MPTP mice treated with Dutasteride 5 and 12.5 mg/kg had higher striatal DA and metabolites (DOPAC and HVA) contents with a decrease of metabolites/DA ratios compared to saline-treated MPTP mice. Finasteride had no protective effect on striatal DA contents. Tyrosine hydroxylase (TH) mRNA levels measured by in situ hybridization in the substantia nigra pars compacta were unchanged. Dutasteride at 12.5 mg/kg reduced the effect of MPTP on specific binding to striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) measured by autoradiography. MPTP reduced compared to controls plasma testosterone (T) and dihydrotestosterone (DHT) concentrations measured by liquid chromatography-tandem mass spectrometry; Dutasteride and Finasteride increased plasma T levels while DHT levels remained low. In summary, our results showed that a 5α-reductase inhibitor, Dutasteride has neuroptotective activity preventing in male mice the MPTP-induced loss of several dopaminergic markers. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 05/2015; 97. DOI:10.1016/j.neuropharm.2015.05.015 · 5.11 Impact Factor
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