The Effect of Spider Toxin PhTx3-4, ω-Conotoxins MVIIA and MVIIC on Glutamate Uptake and on Capsaicin-Induced Glutamate Release and [Ca2+]i in Spinal cord Synaptosomes

Glutamate release, particularly in pathologic conditions, may result in cellular swelling. The authors studied the effects of glutamate, N-methyl-d-aspartate (NMDA), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on extracellular pH (pHe), extracellular potassium concentration ([K+]e), and changes in extracellular space (ECS) diffusion parameters (volume fraction α, tortuosity λ) resulting from cellular swelling. In the isolated spinal cord of 4-to 12-day-old rats, the application of glutamate receptor agonists induced an increase in [K+]e, alkaline-acid shifts, a substantial decrease in α, and an increase in λ. After washout of the glutamate receptor agonists, α either returned to or overshot normal values, whereas λ remained elevated. Pretreatment with 20 mmol/L Mg++, MK801, or CNQX blocked the changes in diffusion parameters, [K+]e and pHe evoked by NMDA or AMPA. However, the changes in diffusion parameters also were blocked in Ca2+-free solution, which had no effect on the [K+]e increase or acid shift. The authors conclude that increased glutamate release may produce a large, sustained and [Ca2+]e-dependent decrease in α and increase in λ. Repetitive stimulation and pathologic states resulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotoxicity and neuronal damage.

Download Full-text

Ischemic Preconditioning Reveals that GLT1/EAAT2 Glutamate Transporter is a Novel PPARγ Target Gene Involved in Neuroprotection

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600438 ◽

2007 ◽

Vol 27 (7) ◽

pp. 1327-1338 ◽

Cited By ~ 103

Author(s):

Cristina Romera ◽

Olivia Hurtado ◽

Judith Mallolas ◽

Marta P Pereira ◽

Jesús R Morales ◽

...

Keyword(s):

Nervous System ◽

Ischemic Preconditioning ◽

Transcriptional Activity ◽

Target Gene ◽

Glutamate Uptake ◽

Glutamate Release ◽

Glutamate Transporter ◽

Glutamate Transport ◽

Extracellular Glutamate ◽

Pparγ Agonist

Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARγ antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1% ± 3.4% versus 97.7% ± 5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8% ± 5.9% versus 85.9% ± 7.9% of OGD-induced glutamate release in IPC and IPC + T0070907 1 μmol/L, respectively, n = 6 to 12, P < 0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P < 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3% ± 7.9% and 65.5% ± 15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 μmol/l, respectively, n = 6 to 12, P < 0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARγ leading to neuroprotection by increasing glutamate uptake.

Download Full-text

In vitroactivation of GAT1 transporters expressed in spinal cord gliosomes stimulates glutamate release that is abnormally elevated in the SOD1/G93A(+) mouse model of amyotrophic lateral sclerosis

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2010.06628.x ◽

2010 ◽

Vol 113 (2) ◽

pp. 489-501 ◽

Cited By ~ 32

Author(s):

Marco Milanese ◽

Simona Zappettini ◽

Emanuela Jacchetti ◽

Tiziana Bonifacino ◽

Chiara Cervetto ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Glutamate Release ◽

Lateral Sclerosis ◽

Sod1 G93a Mouse

Download Full-text

Glutamate Release by Reversed Glutamate Uptake Is Inhibited by Arachidonic Acid

Excitatory Amino Acids and Second Messenger Systems ◽

10.1007/978-3-662-22666-7_5 ◽

1991 ◽

pp. 65-71 ◽

Cited By ~ 2

Author(s):

Marek Szatkowski ◽

Boris Barbour ◽

David Attwell

Keyword(s):

Arachidonic Acid ◽

Glutamate Uptake ◽

Glutamate Release

Download Full-text

NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes

Cells ◽

10.3390/cells8050400 ◽

2019 ◽

Vol 8 (5) ◽

pp. 400 ◽

Cited By ~ 6

Author(s):

Shaimaa Mahmoud ◽

Marjan Gharagozloo ◽

Camille Simard ◽

Abdelaziz Amrani ◽

Denis Gris

Keyword(s):

Glutamate Uptake ◽

Glutamate Release ◽

Neuronal Firing ◽

Glutamate Excitotoxicity ◽

Cns Inflammation ◽

Atp Production ◽

Inflammatory Conditions ◽

Mitochondrial Functions ◽

The Central Nervous System ◽

First Time

Uptake of glutamate from the extracellular space and glutamate release to neurons are two major processes conducted by astrocytes in the central nervous system (CNS) that protect against glutamate excitotoxicity and strengthen neuronal firing, respectively. During inflammatory conditions in the CNS, astrocytes may lose one or both of these functions, resulting in accumulation of the extracellular glutamate, which eventually leads to excitotoxic neuronal death, which in turn worsens the CNS inflammation. NLRX1 is an innate immune NOD-like receptor that inhibits the major inflammatory pathways. It is localized in the mitochondria and was shown to inhibit cell death, enhance ATP production, and dampen oxidative stress. In the current work, using primary murine astrocyte cultures from WT and Nlrx1-/- mice, we demonstrate that NLRX1 potentiates astrocytic glutamate uptake by enhancing mitochondrial functions and the functional activity of glutamate transporters. Also, we report that NLRX1 inhibits glutamate release from astrocytes by repressing Ca2+-mediated glutamate exocytosis. Our study, for the first time, identified NLRX1 as a potential regulator of glutamate homeostasis in the CNS.

Download Full-text

Acute Low Dose of Trazodone Recovers Glutamate Release Efficiency and mGlu2/3 Autoreceptor Impairments in the Spinal Cord of Rats Suffering From Chronic Sciatic Ligation

Frontiers in Pharmacology ◽

10.3389/fphar.2020.01108 ◽

2020 ◽

Vol 11 ◽

Author(s):

Francesca Cisani ◽

Alessandra Roggeri ◽

Guendalina Olivero ◽

Beatrice Garrone ◽

Serena Tongiani ◽

...

Keyword(s):

Spinal Cord ◽

Low Dose ◽

Glutamate Release

Download Full-text

Presynaptic TRPA1 activation enhances glutamate release onto substantia gelatinosa neurons of the adult rat spinal cord

Neuroscience Research ◽

10.1016/j.neures.2007.06.781 ◽

2007 ◽

Vol 58 ◽

pp. S180

Author(s):

Masafumi Kosugi ◽

Terumasa Nakatsuka ◽

Tsugumi Fujita ◽

Takahiro Aoyama ◽

Eiichi Kumamoto

Keyword(s):

Spinal Cord ◽

Glutamate Release ◽

Substantia Gelatinosa ◽

Rat Spinal Cord ◽

Adult Rat ◽

Adult Rat Spinal Cord

Download Full-text

Increased Expression of Cyclooxygenase and Nitric Oxide Isoforms, and Exaggerated Sensitivity to Prostaglandin E2, in the Rat Lumbar Spinal Cord 3 Days after L5–L6 Spinal Nerve Ligation

Anesthesiology ◽

10.1097/00000542-200602000-00019 ◽

2006 ◽

Vol 104 (2) ◽

pp. 328-337 ◽

Cited By ~ 34

Author(s):

Darren D. O’Rielly ◽

Christopher W. Loomis

Keyword(s):

Nitric Oxide ◽

Spinal Cord ◽

Neuropathic Pain ◽

Glutamate Release ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Withdrawal Threshold ◽

Enhanced Sensitivity ◽

Sham Surgery ◽

Inducible Nos

Background Spinal prostaglandins seem to be important in the early pathogenesis of experimental neuropathic pain. Here, the authors investigated changes in the expression of cyclooxygenase and nitric oxide synthase (NOS) isoforms in the lumbar, thoracic, and cervical spinal cord and the pharmacologic sensitivity to spinal prostaglandin E2 (PGE2) after L5-L6 spinal nerve ligation (SNL). Methods Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery 3 days before experimentation. Paw withdrawal threshold was monitored for up to 20 days. Immunoblotting, spinal glutamate release, and behavioral testing were examined 3 days after SNL. Results Allodynia (paw withdrawal threshold < or = 4 g) was evident 1 day after SNL and remained stable for 20 days. Paw withdrawal threshold was unchanged (P > 0.05) from baseline (> 15 g) after sham surgery except for a small but significant decrease on day 20. Cyclooxygenase 2, neuronal NOS, and inducible NOS were significantly increased in the ipsilateral lumbar dorsal horn after SNL. Expression in the contralateral dorsal horn and ventral horns (lumbar segments) or bilaterally (thoracic and cervical segments) was unchanged from sham controls. This was accompanied by a significant decrease in both the EC50 of PGE2-evoked glutamate release and the ED50 of PGE2 on brush-evoked allodynia. Enhanced sensitivity to PGE2 was localized to lumbar segments of SNL animals and attenuated by SC-51322 or S(+)-ibuprofen, but not R(-)-ibuprofen (100 mum). Conclusion The increased expression of cyclooxygense-2, neuronal NOS, and inducible NOS and the enhanced sensitivity to PGE2 in spinal segments affected by SNL support the hypothesis that spinal prostanoids play an early pathogenic role in experimental neuropathic pain.

Download Full-text