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      Involvement of Glutamate Transporter-1 in Neuroprotection against Global Brain Ischemia-Reperfusion Injury Induced by Postconditioning in Rats

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          Abstract

          Ischemic postconditioning refers to several transient reperfusion and ischemia cycles after an ischemic event and before a long duration of reperfusion. The procedure produces neuroprotective effects. The mechanisms underlying these neuroprotective effects are poorly understood. In this study, we found that most neurons in the CA1 region died after 10 minutes of ischemia and is followed by 72 hours of reperfusion. However, brain ischemic postconditioning (six cycles of 10 s/10 s reperfusion/re-occlusion) significantly reduced neuronal death. Significant up-regulation of Glutamate transporter-1 was found after 3, 6, 24, 72 hours of reperfusion. The present study showed that ischemic postconditioning decreases cell death and that upregulation of GLT-1 expression may play an important role on this effect.

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          Protective role of reactive astrocytes in brain ischemia.

          Takeshi Yabe, Christina Nodin, Andrea Lundkvist … (2008)
          Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.
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            Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes.

            Pankaj Gupta, Devanand Sarkar, Zhao Su … (2008)
            Glutamate is an essential neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters primarily expressed in astroglial cells. Dysfunction of EAAT2 is implicated in acute and chronic neurological disorders, including stroke/ischemia, temporal lobe epilepsy, amyotrophic lateral sclerosis, Alzheimer disease, human immunodeficiency virus 1-associated dementia, and growth of malignant gliomas. Ceftriaxone, one of the beta-lactam antibiotics, is a stimulator of EAAT2 expression with neuroprotective effects in both in vitro and in vivo models based in part on its ability to inhibit neuronal cell death by glutamate excitotoxicity. Based on this consideration and its lack of toxicity, ceftriaxone has potential to manipulate glutamate transmission and ameliorate neurotoxicity. We investigated the mechanism by which ceftriaxone enhances EAAT2 expression in primary human fetal astrocytes (PHFA). Ceftriaxone elevated EAAT2 transcription in PHFA through the nuclear factor-kappaB (NF-kappaB) signaling pathway. The antibiotic promoted nuclear translocation of p65 and activation of NF-kappaB. The specific NF-kappaB binding site at the -272 position of the EAAT2 promoter was responsible for ceftriaxone-mediated EAAT2 induction. In addition, ceftriaxone increased glutamate uptake, a primary function of EAAT2, and EAAT2 small interference RNA completely inhibited ceftriaxone-induced glutamate uptake activity in PHFA. Taken together, our data indicate that ceftriaxone is a potent modulator of glutamate transport in PHFA through NF-kappaB-mediated EAAT2 promoter activation. These findings suggest a mechanism for ceftriaxone modulation of glutamate transport and for its potential effects on ameliorating specific neurodegenerative diseases through modulation of extracellular glutamate.
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              Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics.

              Eduardo Candelario-Jalil (2009)
              Ischemic stroke triggers a complex and highly interconnected cascade of cellular and molecular events. Early events induced following ischemic injury, including excitotoxicity, calcium overload and oxidative stress, rapidly result in cell death in the infarct core. Later events, such as neuroinflammation and apoptosis, are relevant to the death of the ischemic penumbra. Drugs that limit delayed-injury events have a wide therapeutic window for protection; however, the damaging events of the ischemic cascade will eventually prevail if reperfusion is not achieved within minutes after ischemia. The combination of thrombolytics with protective drugs may provide a promising therapy in the management of stroke. Targeting all components of the neurovascular unit, rather than just the neuron, should be a priority in stroke research, and agents that block multiple events of the injury cascade are more likely to provide cerebroprotection. Understanding when the brain begins the transition from injury to repair could have important implications for stroke therapy. Several ischemic mediators have dual roles, with detrimental acute effects, but beneficial effects in the repair phase; therefore, extending experimental stroke investigations to an analysis of the long-term outcome is important. This review provides a critical evaluation of promising therapeutic strategies for ischemic stroke, and a translational perspective on how to improve success in the development of novel pharmaceuticals for cerebral ischemia.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 3 November 2010
                Publication date Collection: 2010
                Volume: 11
                Issue: 11
                Pages: 4407-4416
                Affiliations
                [1 ] Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; E-Mails: zhang951154@ 123456sina.com (W.Z.); 553909021@ 123456qq.com (Y.M.); kingwww629@ 123456126.com (B.W.); 13958354209@ 123456139.com (Q.L.)
                [2 ] Department of Neurosurgery, YuYao People’s Hospital, Zhejiang Province, 315400, China; E-Mail: zsq8989@ 123456yahoo.com (S.Z.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: Qiuzhoub@ 123456hotmail.com ; Tel.: +86-21-58752345 ext 3748; Fax: 86-21-58394262.
                Article
                Publisher ID: ijms-11-04407
                DOI: 10.3390/ijms11114407
                PMC ID: 3000089
                PubMed ID: 21151445
                SO-VID: 2b2ce052-9ea2-4cbd-9f73-b00ab26e9d38
                Copyright © © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
                License:

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 17 September 2010
                Date revision received : 1 October 2010
                Date accepted : 22 October 2010
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: brain ischemia reperfusion injury,glutamate transporter 1(glt-1),ischemic postconditioning,neuroprotection
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: brain ischemia reperfusion injury, glutamate transporter 1(glt-1), ischemic postconditioning, neuroprotection

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