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

ABSTRACT 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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    • "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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    • "Neuroactive steroids are molecules acting in the nervous system including steroids produced by the nervous system (i.e., neurosteroids) and hormonal steroids coming from classical steroidogenic tissues (i.e., gonads and adrenal glands) [1]. Several reviews have extensively considered and discussed this topic in the central nervous system (CNS), because the first observations were obtained in the brain [2] [3] [4] [5] [6] [7]. However, more recent results have indicated that the peripheral nervous system (PNS) also synthesizes and metabolizes neuroactive steroids and is a target for these molecules. "
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    ABSTRACT: In the present review we summarize observations to date supporting the concept that neuroactive steroids are synthesized in the peripheral nervous system, regulate the physiology of peripheral nerves and exert notable neuroprotective actions. Indeed, neuroactive steroids have been recently proposed as therapies for different types of peripheral neuropathy, like for instance those occurring during aging, chemotherapy, physical injury and diabetes. Moreover, pharmacological tools able to increase the synthesis of neuroactive steroids might represent new interesting therapeutic strategy to be applied in case of peripheral neuropathy. Copyright © 2015. Published by Elsevier Inc.
    Steroids 03/2015; DOI:10.1016/j.steroids.2015.03.014 · 2.64 Impact Factor
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