Blockade of Glutamate Release from Microglia Attenuates Experimental Autoimmune Encephalomyelitis in Mice

Jin, Shijie; Takeuchi, Hideyuki; Yawata, Izumi; Harada, Yoshio; Sonobe, Yoshifumi; Doi, Yukiko; Liang, Jianfeng; Li, Hua; Yasuoka, Satoko; Zhou, Yan; Noda, Mariko; Koyama, Jun; Mizuno, Tetsuya; Suzumura, Akio

doi:10.1620/tjem.217.87

Cited by 87 publications

(73 citation statements)

References 19 publications

(40 reference statements)

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“…Activated HCs have been involved in the release of gliotransmitters such as ATP and glutamate as well as chemokines that have deleterious consequences on neurons as reported in murine models of AD [18][19][20], experimental allergic encephalomyelitis [21], amyotrophic lateral sclerosis [20,22] and neuropathic pain [23,24]. In our study, it has also been demonstrated that activated HCs can allow Ca 2+ influx, contributing to a maintenance of high [Ca 2+ ]i.…”

Section: Journal Of Cell Signalingsupporting

confidence: 73%

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Yi¹,

Koulakoff²,

Giaume³

2017

J Cell Signal

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CommentaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly and characterized by progressive memory loss, behavioral deficits and significant personality alterations [1,2]. The histopathological hallmarks of AD include Aβ plaques, neurofibrillary tangles, neuronal death and synapse loss. One significant feature of Aβ accumulation is the strong reactive gliosis associated with the Aβ plaques themselves [3,4], however, understanding of the properties and functions of astrocytes in AD has only begun to emerge in recent years.In the brain, astrocytes possess the highest levels of connexin (Cx) expression, with Cx43 and Cx30 being the most abundant [5,6]. Cxs are the proteins that form gap junction channels (GJCs) and hemichannels (HCs). Besides Cxs, HCs can be formed by another family of functionally related proteins, pannexins (Panxs), which share the same transmembrane topology as Cxs but have divergent primary sequences [7]. Cxs and Panxs oligomerize into hexameres that isolate a large non-selective pore in the membrane allowing for the diffusion of small molecules (e.g. ions, small signaling molecules and metabolic substrates) between the cell cytoplasm and the extracellular medium. In addition, most Cx HCs dock head-to-head between adjacent cells to form intercellular channels that constitute GJCs, while endogenously expressed Panx HCs do not [8,9]. In the brain, astrocytes provide trophic and metabolic support to neurons throughout the astrocytic network via gap junction communication which comprise of over several hundreds of astrocytes [10]. In brain pathologies, for instance in AD, reactive astrogliosis has been associated with changes in the expression and function of connexins. Increased expression of Cxs has been found in astrocytes that are in contact with amyloid plaques in vivo within the brains of AD patients and also in AD animal models. The most prominent indication of connexin changes in Alzheimer's disease is that increased immunoreactivity of Cx43 has been found at Aβ plaque levels in the post-mortem brains of AD patients, which coincides with the presence of gap junctions between astrocytic processes that are adjacent to dystrophic neuronal processes that are present in plaque areas at the ultrastructural level [11]. This Cx43 puncta enrichment has also been found within cadaveric brain sections from AD patients and is detected intermingled with strongly GFAP-positive astrocytic processes that infiltrate Aβ plaques [12]. These features have also been shown to be present in Cx30, though to a lower extent. This is also the case in AD animal models. In a murine model of familial AD (APPSwe/PS1dE9; or termed APP/PS1), these transgenic mice exhibit a variety of changes, including an increase in Cx43 or Cx30 immunoreactivity at Aβ plaque levels in the hippocampus and cortex of APP/PS1 mice older than 4 months. These connexin immunoreactivities have been found to be concentrated in bright and large puncta at astrocytic processes that infiltrate the plaque core, and are encircled...

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Section: Journal Of Cell Signalingsupporting

confidence: 73%

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Yi¹,

Koulakoff²,

Giaume³

2017

J Cell Signal

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“…In addition, several studies show increased dye uptake or molecule release (e.g., ATP, glutamate) in activated microglia [192, 204, 207–209], but the use of Cx and Panx HC blockers (e.g., carbenoxolone) does not dissect the molecular entity that mediates the dye uptake. However, these experiments unveil that Cx and Panx HCs may contribute to neuronal death and host defense against pathogen infections.…”

Section: Expression Of Cxs In Antigen-presenting Cellsmentioning

confidence: 99%

“…The latter seems to be mediated by IL-1 [208, 209]. In addition, recent studies show that HC blockers delay the development of Alzheimer' disease, amyotrophic lateral sclerosis, and multiple sclerosis in murine models of these diseases [204, 207], suggesting that HC blockers might be useful as a therapeutical approach to the treatment of these diseases. Interestingly, it was shown that carbenoxolone delays the onset of multiple sclerosis in mice by preventing the release of IL-23 from microglia and the polarization of Th17 cells [210].…”

Section: Expression Of Cxs In Antigen-presenting Cellsmentioning

confidence: 99%

Regulation of Hemichannels and Gap Junction Channels by Cytokines in Antigen-Presenting Cells

Saéz

Shoji

Aguirre

et al. 2014

Mediators of Inflammation

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Autocrine and paracrine signals coordinate responses of several cell types of the immune system that provide efficient protection against different challenges. Antigen-presenting cells (APCs) coordinate activation of this system via homocellular and heterocellular interactions. Cytokines constitute chemical intercellular signals among immune cells and might promote pro- or anti-inflammatory effects. During the last two decades, two membrane pathways for intercellular communication have been demonstrated in cells of the immune system. They are called hemichannels (HCs) and gap junction channels (GJCs) and provide new insights into the mechanisms of the orchestrated response of immune cells. GJCs and HCs are permeable to ions and small molecules, including signaling molecules. The direct intercellular transfer between contacting cells can be mediated by GJCs, whereas the release to or uptake from the extracellular milieu can be mediated by HCs. GJCs and HCs can be constituted by two protein families: connexins (Cxs) or pannexins (Panxs), which are present in almost all APCs, being Cx43 and Panx1 the most ubiquitous members of each protein family. In this review, we focus on the effects of different cytokines on the intercellular communication mediated by HCs and GJCs in APCs and their impact on purinergic signaling.

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“…These results suggest a fundamental role of glutaminase in HIV-induced neurotoxicity. Glutaminase-mediated glutamate release from microglia was also shown to occur in models of multiple sclerosis [14] and ischemia [15], suggesting glutaminase inhibition could be of broad therapeutic interest for neuroinflammatory and neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 99%

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

Thomas

Rojas

Tanega

et al. 2013

Biochemical and Biophysical Research Communications

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Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC1280)) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease.

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Blockade of Glutamate Release from Microglia Attenuates Experimental Autoimmune Encephalomyelitis in Mice

Cited by 87 publications

References 19 publications

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Regulation of Hemichannels and Gap Junction Channels by Cytokines in Antigen-Presenting Cells

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

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