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      Delayed treatment of α5 GABAA receptor inverse agonist improves functional recovery by enhancing neurogenesis after cerebral ischemia-reperfusion injury in rat MCAO model

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      Author(s): 1 , 2 , 3 , 3 , 1 ,
      Publication date (Electronic):
      Journal: Scientific Reports
      Publisher: Nature Publishing Group UK

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          Abstract

          Development of effective therapeutics and treatment strategy to promote recovery after cerebral ischemia-reperfusion injury necessitates further understandings of the complex pathophysiology of ischemic stroke. Given that α5-GABA AR inhibition has been shown to be involved in functional recovery after stroke, the present study was designed to evaluate the effects of treatment timing of α5 GABA AR inhibition on post-middle cerebral artery occlusion (MCAO) functional recovery. To this end, we examined the effects of L655,708 (α5 GABA AR inverse agonist) treatment at 3 or 7 days post-ischemia on apoptosis and neurogenesis in the peri-infarct region, brain infarction size, as well as modified neurological severity score (mNSS) and rotarod test time in rats. Consistent with previous reports, we found that when the treatment of L655,708 was initiated at post-MCAO day 3, it did not alter the functional recovery in rats. However, when the treatment of L655,708 was initiated at post-MCAO day 7, it demonstrated beneficial effects on functional recovery in rats. Interestingly, this phenomenon was not associated with altered brain infarction size nor with changes in brain cell apoptosis. However, we found that delayed treatment of L655,708 at post-MCAO day 7 significantly increased neurogenesis in peri-infarct zone in rats. These results suggested that removing α5 GABA AR-mediated tonic inhibition after cerebral ischemia-reperfusion injury may be an effective therapeutic strategy for promoting functional recovery from stroke.

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

          Shevin T. Jacob, Rachel Jurd, S Moss (2008)
          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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            Neurofibromin regulation of ERK signaling modulates GABA release and learning.

            Yijun Cui, Rui M. Costa, Geoffrey G. Murphy … (2008)
            We uncovered a role for ERK signaling in GABA release, long-term potentiation (LTP), and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for learning disabilities in neurofibromatosis type I (NF1). Our results demonstrate that neurofibromin modulates ERK/synapsin I-dependent GABA release, which in turn modulates hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased GABA release in the hippocampus, and this was reversed by pharmacological downregulation of ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a subthreshold dose of a GABA(A) antagonist. Accordingly, Cre deletions of Nf1 showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP, and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning.
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              Cellular and molecular mechanisms of neural repair after stroke: making waves.

              S Thomas Carmichael (2006)
              Stroke is associated with a limited degree of functional recovery. Imaging studies in humans have shown that reorganization in periinfarct and connected cortical areas most closely correlates with functional recovery after stroke. On a cellular level, two major regenerative events occur in periinfarct cortex: axons sprout new connections and establish novel projection patterns, and newly born immature neurons migrate into periinfarct cortex. Stroke induces a unique microenvironment for axonal sprouting in periinfarct cortex, in which growth-inhibitory molecules are reduced for 1 month after the infarct. During this period, neurons activate growth-promoting genes in successive waves. Neurogenesis also occurs through waves of migration of immature neurons from their origin in the subventricular zone into periinfarct cortex. This migration is mediated, in part, by the cytokine erythropoietin. These data indicate that the cellular environment after stroke is far from one of just death and destruction, but rather involves a longer evolving process of neuronal regeneration. Poststroke neuronal regeneration is characterized by waves of specific cellular and molecular events. Manipulating these waves of regeneration may provide for novel therapies that will improve recovery after stroke.
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                Author and article information

                Contributors
                Yu-Ping Peng:
                ORCID: http://orcid.org/0000-0002-6685-3554
                yuping_p@yahoo.com
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 19 February 2019
                Publication date PMC-release: 19 February 2019
                Publication date Collection: 2019
                Volume: 9
                Electronic Location Identifier: 2287
                Affiliations
                [1 ]Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 P. R. China
                [2 ]ISNI 0000 0000 8547 6673, GRID grid.411647.1, Neurosurgery, Affiliated Hospital of Inner Mongolia University for the Nationalities, ; Tongliao City, Inner Mongolia 028000 P. R. China
                [3 ]Neurosurgery, First Hospital, Jia Mu Si University, Jiamusi, 154007 P. R. China
                Author information
                http://orcid.org/0000-0002-6685-3554
                Article
                Publisher ID: 38750
                DOI: 10.1038/s41598-019-38750-0
                PMC ID: 6381084
                PubMed ID: 30783142
                SO-VID: daef9ef5-9a4c-4584-9803-c668bec7dcbd
                Copyright © © The Author(s) 2019
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 9 August 2018
                Date accepted : 18 December 2018
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Uncategorized
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