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      Structure-Dependent Activity of Natural GABA(A) Receptor Modulators

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          Abstract

          GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This pentameric structure not only allows different receptor binding sites, but also various types of ligands, such as orthosteric agonists and antagonists, positive and negative allosteric modulators, as well as second-order modulators and non-competitive channel blockers. A fact, that is also displayed by the variety of chemical structures found for both, synthetic as well as nature-derived GABA(A)-receptor modulators. This review covers the literature for natural GABA(A)-receptor modulators until the end of 2017 and discusses their structure-activity relationship.

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          Most cited references162

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          Neurosteroids: endogenous regulators of the GABA(A) receptor.

          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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            GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition.

            GABA (gamma-aminobutyric acid) type A receptors (GABA(A)Rs) mediate most fast synaptic inhibition in the mammalian brain, controlling activity at both the network and the cellular levels. The diverse functions of GABA in the CNS are matched not just by the heterogeneity of GABA(A)Rs, but also by the complex trafficking mechanisms and protein-protein interactions that generate and maintain an appropriate receptor cell-surface localization. In this Review, we discuss recent progress in our understanding of the dynamic regulation of GABA(A)R composition, trafficking to and from the neuronal surface, and lateral movement of receptors between synaptic and extrasynaptic locations. Finally, we highlight a number of neurological disorders, including epilepsy and schizophrenia, in which alterations in GABA(A)R trafficking occur.
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              The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury.

              The purpose of the present experiment was to examine the effectiveness of a modified rotarod test in detecting motor deficits following mild and moderate central fluid percussion brain injury. In addition, this investigation compared the performance of the rotarod task with two other commonly used measures of motor function after brain injury (beam-balance and beam-walking latencies). Rats were either injured with a mild (n = 14) or moderate (n = 8) level of fluid percussion injury or were surgically prepared but not injured (n = 8). All rats were assessed on all tasks for 5 days following their respective treatments. Results revealed that both the mild and moderate injury levels produced significant deficits in the ability of the animals to perform the rotarod task. Performance on the beam-balance and beam-walking tasks were not significantly impaired at the mild injury level. It was only at the moderate injury level that the beam-balance and beam-walking tasks detected deficits in motor performance. This result demonstrated that the rotarod task was a sensitive index of injury-induced motor dysfunction following even mild fluid percussion injury. A power analysis of the three tasks indicated that statistically significant group differences could be obtained with the rotarod task with much smaller sample sizes than with the beam-balance and beam-walking tasks. Performance on the rotarod, beam-walk, and beam-balance tasks were compared and evaluated by a multivariate stepdown analysis (multiple analysis of variance followed by univariate analyses of covariance). This analysis indicated that the rotarod task measures aspects of motor impairment that are not assessed by either the beam-balance or beam-walking latency. These findings suggest that compared to the beam-balance and beam-walking tasks, the rotarod task is a more sensitive and efficient index for assessing motor impairment produced by brain injury.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                MDPI
                1420-3049
                22 June 2018
                July 2018
                : 23
                : 7
                : 1512
                Affiliations
                Department of Pharmaceutical Biology, Kiel University, Gutenbergstraße 76, 24118 Kiel, Germany; scicek@ 123456pharmazie.uni-kiel.de ; Tel.: +49-431-880-1077
                Author information
                https://orcid.org/0000-0002-3038-8523
                Article
                molecules-23-01512
                10.3390/molecules23071512
                6100244
                29932138
                3bc9ccf9-45d9-4b85-8dea-cfb06a5003e4
                © 2018 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 May 2018
                : 20 June 2018
                Categories
                Review

                γ-aminobutyric acid,natural product,plant origin,benzodiazepine binding site,anxiolytic,sedative,anesthetic,anticonvulsant

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