Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro

Nelson, R.M; Lambert, David G.; Green, A Richard; Hainsworth, Atticus H.

doi:10.1016/s0006-8993(02)03691-0

Cited by 27 publications

(9 citation statements)

References 47 publications

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“…In the present study, the OGD-induced reversed operation of astrocytic GLT-1 seemed to be a primary cause of the marked elevation in the concentration of Glu. In support of this finding, a recent report using rat cerebrocortical prisms has demonstrated that astrocytic GLAST does not contribute to the ischemia-induced rise of extracellular Glu (Nelson et al, 2003).…”

Section: Discussionsupporting

confidence: 55%

Reversed operation of glutamate transporter GLT‐1 is crucial to the development of preconditioning‐induced ischemic tolerance of neurons in neuron/astrocyte co‐cultures

Kikuchi

Kosugi

Tanaka

et al. 2004

Glia

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Sublethal ischemia leads to increased tolerance against subsequent prolonged cerebral ischemia in vivo. In the present study, we investigated the roles of the astrocytic glutamate (Glu) transporter GLT-1 in preconditioning (PC)-induced neuronal ischemic tolerance in cortical neuron/astrocyte co-cultures. Ischemia in vitro was simulated by subjecting cultures to both oxygen and glucose deprivation (OGD). A sublethal OGD (PC) significantly increased the survival rate of neurons when cultures were exposed to a lethal OGD 24 hr later. The extracellular concentration of Glu increased significantly during PC, and treatment with an inhibitor of NMDA receptors significantly reversed the PC-induced ischemic tolerance of neurons, suggesting that the increase in extracellular concentration of Glu during PC was critical to the development of PC-induced neuronal ischemic tolerance via the activation of NMDA receptors. Treatment with a GLT-1 blocker during PC significantly suppressed this increase in Glu, and antagonized the PC-induced neuronal ischemic tolerance. This study suggested that the reversed operation of GLT-1 was crucial to the development of neuronal ischemic tolerance.2

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Section: Discussionsupporting

confidence: 55%

Reversed operation of glutamate transporter GLT‐1 is crucial to the development of preconditioning‐induced ischemic tolerance of neurons in neuron/astrocyte co‐cultures

Kikuchi

Kosugi

Tanaka

et al. 2004

Glia

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“…All these observations clearly establish that d ‐aspartate efflux is elicited by both, depolarization/dissipation of the ionic gradients and cell swelling, and proceeds via two different routes, as has been previously demonstrated by Rutledge and Kimelberg (1996). The same conclusion has been reached after substantial evidence regarding glutamate efflux in a variety of experimental models of ischemia, in vitro and in vivo (Nelson et al. 2003; Phillis and O’Regan 2003; Mongin and Kimelberg 2004; Swanson et al.…”

Section: Discussionsupporting

confidence: 79%

Thrombin potentiates d‐aspartate efflux from cultured astrocytes under conditions of K⁺ homeostasis disruption

Vázquez-Juárez¹,

Hernández-Benítez²,

López-Domínguez³

et al. 2009

Journal of Neurochemistry

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Thrombin levels increase in brain during ischemia and hemorrhagic episodes, and may contribute to excitotoxic neural damage. This study examined the effect of thrombin on glutamate efflux from rat cortical cultured astrocytes using 3H‐d‐aspartate as radiotracer. The glutamate efflux was initiated by addition of 100 mM K+ plus 1 mM ouabain (K/O) to replicate extracellular and intracellular ionic changes that occur during cerebral ischemia. Upon exposure to K/O, astrocytes swelled slowly and progressively with no evidence of volume regulation. The K/O‐induced swelling was inhibited by 65% with bumetanide and 25% with BaCl2, suggesting contribution of Na+/K+/Cl− co‐transporter and Kir channels. K/O‐elicited 3H‐d‐aspartate that consisted of two phases. The first transient component of the release corresponded to 13.5% of total 3H‐d‐aspartate loaded. It was markedly reduced (61%) by the glutamate transporter blocker DL‐threo‐b‐Benzyloxyaspartic acid and weakly inhibited (21%) by the volume‐sensitive anion channel blocker 4‐[(2‐Butyl‐6,7dichloro‐2‐cyclopentyl‐2,3‐dihidro‐1oxo‐1H‐inden‐5‐yl)oxy] butanoic acid (DCPIB). During the second sustained phase of release, cells lost 45% of loaded of 3H‐d‐aspartate via a mechanism that was insensitive to DL‐threo‐b‐Benzyloxyaspartic acid but nearly completely suppressed by DCPIB. Thrombin (5 U/mL) had only marginal effects on the first phase but strongly potentiated (more than two‐fold) 3H‐d‐aspartate efflux in the second phase. The effect of thrombin effect was proportional to cell swelling and completely suppressed by DCPIB. Overall our data showed that under K/O swelling conditions, thrombin potently enhance glutamate release via volume‐sensitive anion channel. Similar mechanisms may contribute to brain damage in neural pathologies which are associated with cell swelling, glutamate efflux and increased thrombin levels.

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“…Increased glutamate release occurs in multiple organs subjected to ischemia (41)(42)(43) and glutamic acid decarboxylase, the critical enzyme-converting glutamate to GABA does not require oxygen, and is ubiquitously expressed in tissues such as brain, heart, kidney, and lung (44,45). In the current study, the presence of glutamic acid decarboxylase in neutrophils was documented by Western blot analysis.…”

Section: Discussionmentioning

confidence: 67%

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

Rane

Gozal

Butt

et al. 2005

The Journal of Immunology

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Serine/threonine kinase Akt, or protein kinase B, has been shown to regulate a number of neutrophil functions. We sought to identify Akt binding proteins in neutrophils to provide further insights into understanding the mechanism by which Akt regulates various neutrophil functions. Proteomic and immunoprecipitation studies identified γ-amino butyric acid (GABA) type B receptor 2 (GABABR2) as an Akt binding protein in human neutrophils. Neutrophil lysates subjected to Akt immunoprecipitation followed by immunoblotting with anti-GABABR2 demonstrated Akt association with the intact GABABR. Similar results were obtained when reciprocal immunoprecipitations were performed with anti-GABABR2 Ab. Additionally, GABABR2 and Akt colocalization was demonstrated by confocal microscopy. A GABABR agonist, baclofen, activated Akt and stimulated neutrophil-directed migration in a PI3K-dependent manner, whereas CGP52432, a GABABR antagonist blocked such effects. Baclofen, stimulated neutrophil chemotaxis and tubulin reorganization in a PI3K-dependent manner. Additionally, a GABABR agonist failed to stimulate neutrophil superoxide burst. We are unaware of the association of GABABR with Akt in any cell type. The present study shows for the first time that a brain-specific receptor, GABABR2 is present in human neutrophils and that it is functionally associated with Akt. Intraventricular baclofen pretreatment in rats subjected to a stroke model showed increased migration of neutrophils to the ischemic lesion. Thus, the GABABR is functionally expressed in neutrophils, and acts as a chemoattractant receptor via an Akt-dependent pathway. The GABABR potentially plays a significant role in the inflammatory response and neutrophil-dependent ischemia-reperfusion injury such as stroke.

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Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro

Cited by 27 publications

References 47 publications

Reversed operation of glutamate transporter GLT‐1 is crucial to the development of preconditioning‐induced ischemic tolerance of neurons in neuron/astrocyte co‐cultures

Reversed operation of glutamate transporter GLT‐1 is crucial to the development of preconditioning‐induced ischemic tolerance of neurons in neuron/astrocyte co‐cultures

Thrombin potentiates d‐aspartate efflux from cultured astrocytes under conditions of K⁺ homeostasis disruption

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

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Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro

Cited by 27 publications

References 47 publications

Reversed operation of glutamate transporter GLT‐1 is crucial to the development of preconditioning‐induced ischemic tolerance of neurons in neuron/astrocyte co‐cultures

Reversed operation of glutamate transporter GLT‐1 is crucial to the development of preconditioning‐induced ischemic tolerance of neurons in neuron/astrocyte co‐cultures

Thrombin potentiates d‐aspartate efflux from cultured astrocytes under conditions of K+ homeostasis disruption

γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion

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Thrombin potentiates d‐aspartate efflux from cultured astrocytes under conditions of K⁺ homeostasis disruption