ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 157 citations in OpenAlex.
- Plasma glutamate-modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury-induced acute lung injury.The Journal of experimental medicine · 2013Trial
- Adenosine receptor signaling in vascular diseases: from molecular mechanisms to targeted therapeutics.Acta pharmacologica Sinica · 2026Review
- Adenosine A2A receptor signaling in neuroinflammation, glial modulation, and mechanisms associated with chronic pain.Purinergic signalling · 2026Review
- Adenosine APharmaceuticals (Basel, Switzerland) · 2026Article
- Targeting beta-2 adrenergic receptor attenuates schizophrenia-like behavioral effects induced by ketamine in mice: cAMP/PKA/BDNF-PEA-3 and RIM-1α signaling pathways involvement.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Article
- Adenosine AJournal of neurochemistry · 2026Article
- Adenosine A2A signaling in mood disorders: How far have we come?IBRO neuroscience reports · 2025Article
- Adenosine and adenosine receptors in metabolic imbalance-related neurological issues.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2024Review
- Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats.Aging and disease · 2024Article
- Targeting the adenosine AChinese journal of traumatology = Zhonghua chuang shang za zhi · 2024Review
- 40 Hz light flickering promotes sleep through cortical adenosine signaling.Cell research · 2024Article
- Inhibition of the interaction between microglial adenosine 2A receptor and NLRP3 inflammasome attenuates neuroinflammation posttraumatic brain injury.CNS neuroscience & therapeutics · 2024Article
- Modification of astrocytic Cx43 hemichannel activity in animal models of AD: modulation by adenosine ACellular and molecular life sciences : CMLS · 2023Article
- Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis.CNS neuroscience & therapeutics · 2023Review
- Increased ATP Release and Higher Impact of Adenosine AMolecular neurobiology · 2023Article
- Glutamate Neurotoxicity and Destruction of the Blood-Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies.International journal of molecular sciences · 2022Review
- Contribution of Adenosine in the Physiological Changes and Injuries Secondary to Exposure to Extreme Oxygen Pressure in Healthy Subjects.Biomedicines · 2022Review
- AInternational journal of molecular sciences · 2022Review
- Immune modulation after traumatic brain injury.Frontiers in medicine · 2022Review
- The adenosine AFrontiers in pharmacology · 2022Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
During brain injury, extracellular adenosine and glutamate levels increase rapidly and dramatically. We hypothesized that local glutamate levels in the brain dictates the adenosine-adenosine A(2A) receptor (A(2A)R) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A(2A)R agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid (CGS21680) inhibited lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) activity of cultured microglial cells, an effect that was dependent on the protein kinase A (PKA) pathway. However, in high concentrations of glutamate, CGS21680 increased LPS-induced NOS activity in a protein kinase C (PKC)-dependent manner. Thus, increasing the local level of glutamate redirects A(2A)R signaling from the PKA to the PKC pathway, resulting in a switch in A(2A)R effects from antiinflammatory to proinflammatory. In a cortical impact model of traumatic brain injury (TBI) in mice, brain water contents, behavioral deficits, and expression of tumor necrosis factor-alpha, interleukin-1 mRNAs, and inducible NOS were attenuated by administering CGS21680 at post-TBI time when brain glutamate levels were low, or by administering the A(2A)R antagonist ZM241385 [4-(2-{[5-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl]amino}ethyl)phenol] at post-TBI time when brain glutamate levels were elevated. Furthermore, pre-TBI treatment with the glutamate release inhibitor (S)-4C3HPG [(S)-4-carboxy-3-hydroxyphenylglycine] converted the debilitating effect of CGS21680 administered at post-TBI time with high glutamate level to a neuroprotective effect. This further indicates that the switch in the effect of A(2A)R activation in intact animals from antiinflammatory to proinflammatory is dependent on glutamate concentration. These findings identify a novel role for glutamate in modulation of neuroinflammation and brain injury via the adenosine-A(2A)R system.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.