Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors

Yawata, Izumi; Takeuchi, Hideyuki; Doi, Yukiko; Liang, Jianfeng; Mizuno, Tetsuya; Suzumura, Akio

doi:10.1016/j.lfs.2008.03.010

Cited by 94 publications

(78 citation statements)

References 20 publications

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“…We also revealed that glutamate from activated microglia/macrophage induced excitotoxic neuronal death through NMDA receptor signaling (Takeuchi et al 2006;Yawata et al 2008). Thus, we assessed whether inhibition of gap junction or glutaminase reduced microglial excitoneurotoxicity.…”

Section: Blockade Of Microglial Glutamate Release Rescued Neuronal Dementioning

confidence: 85%

“…We previously demonstrated that activated microglia/ macrophage synthesized glutamate by glutaminase from extracellular glutamine and released it through hemichannels of gap junctions (Takeuchi et al 2006Yawata et al 2008. We also revealed that glutamate from activated microglia/macrophage induced excitotoxic neuronal death through NMDA receptor signaling (Takeuchi et al 2006;Yawata et al 2008).…”

Section: Blockade Of Microglial Glutamate Release Rescued Neuronal Dementioning

confidence: 96%

“…Accumulation of activated microglia/macrophage is a pathological hallmark of active MS lesion, and microglia/macrophage can act as not only antigen-presenting cells but also effector cells to damage CNS cells directly. Especially, excitotoxicity by glutamate released from activated microglia/ macrophage is considered as a major cause of axonal degeneration (Pitt et al 2000;Takeuchi et al 2005;Takeuchi et al 2006;Dutta and Trapp 2007;Yawata et al 2008), and blockade of microglial glutamate release may be an effective therapy to prevent axonal loss. Recent reports showed that IFN-β therapy slowed progression of brain atrophy due to axonal degeneration (Hardmeier et al 2005;Zivadinov et al 2007).…”

mentioning

confidence: 99%

“…Recent studies showed that various cells release small molecules (including ions, ATP, and amino acids) from unpaired hemichannel of gap junction that is openly exposed to the extracellular space (Saez et al 2005). Recently, we have identified that activated microglia/macrophage synthesize glutamate via glutaminase from extracellular glutamine and release it through unpaired hemichannels of gap junctions (Takeuchi et al 2006;Yawata et al 2008). Furthermore, we have also demonstrated that both the glutaminase inhibitor and the gap junction blocker prevented neuronal death in a rodent model of transient ischemic brain injury .…”

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confidence: 99%

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

Jin

Takeuchi

Yawata

et al. 2009

Tohoku J. Exp. Med.

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Section: Blockade Of Microglial Glutamate Release Rescued Neuronal Dementioning

confidence: 85%

Section: Blockade Of Microglial Glutamate Release Rescued Neuronal Dementioning

confidence: 96%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Jin

Takeuchi

Yawata

et al. 2009

Tohoku J. Exp. Med.

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“…inhibits both conductance states, while agents such as carbenoxolone, a gap junction (connexin hemichannel) blocker (Davidson et al, 1986;Spray et al, 2002) with antagonistic potential for P2X 7 R (Iglesias et al, 2008), has a myriad of confounding antiinflammatory (Suzuki et al, 2004a;Cherian et al, 2005;Rana and Dringen, 2007;Véliz et al, 2008;Yawata et al, 2008) and nonselective actions (Rana and Dringen, 2007;Yawata et al, 2008). To distinguish whether P2X 7 R channel or pore was predominantly responsible for driving microglial activation and proliferation, we used a P2X 7 R point mutant, P2X7RG345Y.…”

Section: Atp Stimulation Of P2x 7 R Is Required For Microglial Activamentioning

confidence: 99%

The P2X₇Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X₇R Pore

et al. 2009

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Microglial activation is an integral part of neuroinflammation associated with many neurodegenerative conditions. Interestingly, a number of neurodegenerative conditions exhibit enhanced P2X 7 receptor (P2X 7 R) expression in the neuroinflammatory foci where activated microglia are a coexisting feature. Whether P2X 7 R overexpression is driving microglial activation or, conversely, P2X 7 R overexpression is a consequence of microglial activation is not known. We report that overexpression alone of a purinergic P2X 7 R, in the absence of pathological insults, is sufficient to drive the activation and proliferation of microglia in rat primary hippocampal cultures. The trophic responses observed in microglia were found to be P2X 7 R specific as the P2X 7 R antagonist, oxidized ATP (oxATP), was effective in markedly attenuating microgliosis. oxATP treatment of primary hippocampal cultures expressing exogenous P2X 7 Rs resulted in a significant decrease in the number of activated microglia. P2X 7 R is unusual in exhibiting two conductance states, a cation channel and a plasma membrane pore, and there are no pharmacological agents capable of cleanly discriminating between these two states. We used a point mutant of P2X 7 R (P2X7RG345Y) with intact channel function but ablated pore-forming capacity to establish that the trophic effects of increased P2X 7 R expression are exclusively mediated by the pore conductance. Collectively, and contrary to previous reports describing P2X 7 R as a "death receptor," we provide evidence for a novel trophic role for P2X 7 R pore in microglia.

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Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke

Sharma¹,

Yang²,

Strong³

et al. 2010

J of Neuroscience Research

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Background Although several studies have provided evidence for the therapeutic potential of bone marrow-derived mononuclear cells (MNCs) in animal models of stroke, the mechanisms underlying their benefits remain largely unknown. We have determined the neuroprotective potential of MNCs in primary neuronal cultures exposed to various injuries in vitro. Methods Cortical neurons in culture were exposed to oxygen-glucose deprivation, hypoxia, or hydrogen peroxide and cell death was assayed by MTT, caspase-3 activation or TUNEL labelling at 24 hrs. Cultures were randomized to co-treatment with MNC-derived supernatants or media before injury exposure. In separate experiments, macrophage or microglial cultures were exposed to lipopolypolysacharide (LPS) in the presence and absence of MNC-derived supernatants. Neuronal cultures were then exposed to conditioned media derived from activated macrophages or microglia. Cytokines from the supernantants of MNC cultures exposed to normoxia or hypoxia were also estimated by enzyme-linked immunosorbant assay (ELISA). Results MNC-derived supernatants attenuated neuronal death induced by OGD, hypoxia, hydrogen peroxide, and conditioned macrophage/microglial media and contain a number of trophic factors including IL-10, IGF-1, VEGF, and SDF-1. Conclusion MNCs provide broad neuroprotection against a variety of injuries relevant to stroke.

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Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors

Cited by 94 publications

References 20 publications

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

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

The P2X₇Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X₇R Pore

Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke

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Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors

Cited by 94 publications

References 20 publications

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

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

The P2X7Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X7R Pore

Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke

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The P2X₇Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X₇R Pore