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: 31.38). 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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    • "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 · 4.82 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 · 2.72 Impact Factor
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    • "An additional and partly related explanation could be related to the laminar distribution of steroid-sensitive GABA A R subunits. Indeed, a1, a3 and d subunits are the most sensitive to 3a5a- reduced steroid potentiation (Belelli & Lambert, 2005). Given that a1 is absent from superficial layers (Bohlhalter et al., 1996) and the situation regarding d is still under debate, a3 remains as the most probable steroid-sensitive GABA A R target in the superficial dorsal horn. "
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    ABSTRACT: Corticosterone (CORT) is a glucocorticoid produced by adrenal glands under the control of the hypothalamic–pituitary–adrenal axis. Circulating CORT can enter the central nervous system and be reduced to neuroactive 3α5α-reduced steroids, which modulate GABAA receptors. In the dorsal spinal cord, GABAergic transmission modulates integration of nociceptive information. It has been shown that enhancing spinal inhibitory transmission alleviates hyperalgesia and allodynia. Therefore, the spinal neuronal network is a pivotal target to counteract pain symptoms. Thus, any increase in spinal 3α5α-reduced steroid production enhancing GABAergic inhibition should reduce nociceptive message integration and the pain response. Previously, it has been shown that high levels of plasma glucocorticoids give rise to analgesia. However, to our knowledge, nothing has been reported regarding direct non-genomic modulation of neuronal spinal activity by peripheral CORT. In the present study, we used combined in vivo and in vitro electrophysiology approaches, associated with measurement of nociceptive mechanical sensitivity and plasma CORT level measurement, to assess the impact of circulating CORT on rat nociception. We showed that CORT plasma level elevation produced analgesia via a reduction in C-fiber-mediated spinal responses. In the spine, CORT is reduced to the neuroactive metabolite allotetrahydrodeoxycorticosterone, which specifically enhances lamina II GABAergic synaptic transmission. The main consequence is a reduction in lamina II network excitability, reflecting a selective decrease in the processing of nociceptive inputs. The depressed neuronal activity at the spinal level then, in turn, leads to weaker nociceptive message transmission to supraspinal structures and hence to alleviation of pain.
    European Journal of Neuroscience 11/2014; 41(3). DOI:10.1111/ejn.12796 · 3.67 Impact Factor
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