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, Kôichi; Kosugi, Tatsuro; Tanaka, Motoki; Nakajima, Takayuki; Yamada, Takeshi

doi:10.1002/glia.20114

Cited by 40 publications

(39 citation statements)

References 35 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…17 Ischemic preconditioning depends on the expression of astrocytic GLT-1 and the level of its reverse operation. 18 Because glutamate transporters are dynamic proteins that can release or uptake glutamate, their function depends on their regional and cellular localizations, cerebral energy statuses, and the durations and types of neuronal insults. It is known that the reversal of GLT-1 contributes to ischemia-induced increases in excitatory amino acids in the ischemic core.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

Chu

Sinn

et al. 2007

Stroke

171

167

View full text Add to dashboard Cite

Background and Purpose-Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, ␤-lactam antibiotics, like ceftriaxone (CTX), were reported to induce the upregulation of GLT-1. Here, we investigated ischemic tolerance induction by CTX in an experimental model of focal cerebral ischemia. Methods-CTX (200 mg/kg per day, IP) was administered for 5 consecutive days before transient focal ischemia, which was induced by intraluminal thread occlusion of the middle cerebral artery for 90 minutes or permanently. Results-Repeated CTX injections enhanced GLT-1 mRNA and protein expressions after 3 and 5 days of treatment, respectively. CTX-pretreated animals showed a reduction in infarct volume by 58% (reperfusion) and 39% (permanent), compared with the vehicle-pretreated animals at 24 hours postischemia (PϽ0.01). Lower doses of CTX (20 mg/kg per day and 100 mg/kg per day) reduced infarct volumes to a lesser degree. The injection of GLT-1 inhibitor (dihydrokainate) at 30 minutes before ischemia ameliorated the effect of CTX pretreatment. However, CTX administration at 30 minutes after ischemia produced no significant reduction in infarct volume. CTX reduced the levels of proinflammatory cytokines (tumor necrosis factor-␣, FasL), matrix metalloproteinase (MMP)-9, and activated caspase-9 (PϽ0.01). In addition, CTX-pretreated animals showed better functional recovery at day 1 to week 5 after ischemia (PϽ0.05). Conclusions-This study presents evidence that CTX induces ischemic tolerance in focal cerebral ischemia and that this is mediated by GLT-1 upregulation. (Stroke. 2007;38:177-182.)

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

Chu

Sinn

et al. 2007

Stroke

171

167

View full text Add to dashboard Cite

show abstract

“…We have recently demonstrated that the reversed operation of Glu transporter GLT-1 during subtoxic PC insult is necessary for the development of PC-induced ischemic tolerance of neurons (10). This finding has suggested for the first time that the change in glial function during prior PC is critical to the development of neuronal ischemic tolerance.…”

Section: Introductionmentioning

confidence: 91%

Functional Significance of the Preconditioning-induced Down-regulation of Glutamate Transporter GLT-1 in Neuron/astrocyte Co-cultures

et al. 2005

Self Cite

View full text Add to dashboard Cite

In the brain, prior sublethal ischemia (preconditioning, PC) is known to produce tolerance of neurons to subsequent lethal ischemia. This study aims at elucidating what alterations were induced in neurons and/or astrocytes by PC treatment. The rise in the extracellular concentration of glutamate during ischemia was markedly suppressed by the prior PC treatment. Immunocytochemical and Western blot analyses demonstrated that the expression of the astrocytic glutamate transporter GLT-1 was transiently down-regulated after the PC insult. The PC insult possibly suppressed the neuron-derived factors up-regulating GLT-1. Here we show that PC-induced down-regulation of GLT-1 is crucial for the increased neuronal resistance to subsequent severe ischemic insult.

show abstract

“…Culture methods were described previously in detail (3,4,10,11). In brief, both neurons and astrocytes were prepared from 17-day old embryonic rat cortices and grown in Dulbecco's modified Eagle's medium (DMEM, Gibco, Grand Island, NY) which was supplemented with 10% heat-inactivated fetal bovine serum (FBS), 10%…”

Section: Neuron/astrocyte Co-culturementioning

confidence: 99%

“…Cortical cultures were subjected to oxygen-glucose deprivation (OGD) injury using a protocol described previously (11,12). In brief, cultures were placed in an anaerobic chamber and washed two times with a balanced salt solution (BSS: 116 mM NaCl, 0.8 mM MgSO 4 , 5.4 mM KCl, 1.0 mM NaH 2 PO 4 , 26.2 mM NaHCO 3 , 1.8 mM CaCl 2 , 0.01 mM glycine, and 10 mg/l phenol red) lacking glucose.…”

Section: Oxygen-glucose Deprivationmentioning

confidence: 99%

Nitric Oxide Produced During Sublethal Ischemia Is Crucial for the Preconditioning-Induced Down-Regulation of Glutamate Transporter GLT-1 in Neuron/Astrocyte Co-Cultures

et al. 2006

Self Cite

View full text Add to dashboard Cite

Running head: nitric oxide and preconditioning-induced ischemic tolerance ------------------------------------------------------------------- AbstractIn the brain, prior sublethal ischemia (preconditioning, PC) produces tolerance of neurons to subsequent lethal ischemia. This study aims at elucidating whether and how nitric oxide (NO) produced during PC is involved in the PC-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures. The rise in the extracellular concentration of glutamate during ischemia caused by the reversed uptake of glutamate (Glu) by the astrocytic Glu transporter GLT-1 was markedly suppressed by the prior PC treatment, but the suppression was reversed by treatment with an inhibitor of nitric oxide synthase (NOS) during PC. Immunocytochemical and Western blot analyses demonstrated that the expression of GLT-1 was down-regulated after the PC insult, and this down-regulation was also antagonized by treatment with NOS inhibitors during PC.Here we show that nNOS-derived NO produced during PC was crucial for the down-regulation of astrocytic GLT-1, and this down-regulation coincided with an increased survival rate of neurons.

show abstract

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

Cited by 40 publications

References 35 publications

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

Functional Significance of the Preconditioning-induced Down-regulation of Glutamate Transporter GLT-1 in Neuron/astrocyte Co-cultures

Nitric Oxide Produced During Sublethal Ischemia Is Crucial for the Preconditioning-Induced Down-Regulation of Glutamate Transporter GLT-1 in Neuron/Astrocyte Co-Cultures

Contact Info

Product

Resources

About