Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain

Bai, Wei; Li, Ping; Ning, Yuping; Peng, Yan; Xiong, Ranhua; Yang, Nan; Chen, Xing; Zhou, Yuan‐Guo

doi:10.1016/j.bbrc.2018.03.060

Cited by 9 publications

(9 citation statements)

References 34 publications

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“…The switch in the effect of A 2A R activation from anti‐inflammatory to pro‐inflammatory depends on glutamate concentration 96 . After TBI, inhibition of adenosine receptors increases Na + ‐K + ‐ATPase activity and reduces its interaction with EAATs in isolated brain capillaries, restoring the normal transport function of EAATs 97 . In addition, the high level of blood glutamate after TBI is also closely related to the occurrence and severity of traumatic brain injury‐induced acute lung injury.…”

Section: Potential Intervention Approaches To Restore Glutamate Homeo...mentioning

confidence: 99%

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis

et al. 2023

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Background Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE. Aims To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis. Methods We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance. Results TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective. Discussion Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment. Conclusion It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.

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Section: Potential Intervention Approaches To Restore Glutamate Homeo...mentioning

confidence: 99%

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis

et al. 2023

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“…The activity of the adenosine A2A receptor (ADORA2A), a canonical upstream regulator of the protein kinase A signaling pathway, was also uniquely reduced only within the cortex of TSm rats. Reduction of ADORA2A signaling via pharmacological or genetic approaches significantly improves cognitive outcomes and attenuates cortical and hippocampal lesions, proinflammatory cytokine expression, glutamate release, edema, cell loss, and gliosis in both early and prolonged phases of injury [27][28][29]. Thus, MA may also mediate neuroprotection via acute inactivation of the A2A receptor.…”

Section: Unique Ma-mediated Alterations To Upstream Regulatorsmentioning

confidence: 99%

Potential Neuroprotective Mechanisms of Methamphetamine Treatment in Traumatic Brain Injury Defined by Large-Scale IonStar-Based Quantitative Proteomics

Shen

Zhang

et al. 2021

IJMS

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Although traumatic brain injury (TBI) causes hospitalizations and mortality worldwide, there are no approved neuroprotective treatments, partly due to a poor understanding of the molecular mechanisms underlying TBI neuropathology and neuroprotection. We previously reported that the administration of low-dose methamphetamine (MA) induced significant functional/cognitive improvements following severe TBI in rats. We further demonstrated that MA mediates neuroprotection in part, via dopamine-dependent activation of the PI3K-AKT pathway. Here, we further investigated the proteomic changes within the rat cortex and hippocampus following mild TBI (TM), severe TBI (TS), or severe TBI plus MA treatment (TSm) compared to sham operated controls. We identified 402 and 801 altered proteins (APs) with high confidence in cortical and hippocampal tissues, respectively. The overall profile of APs observed in TSm rats more closely resembled those seen in TM rather than TS rats. Pathway analysis suggested beneficial roles for acute signaling through IL-6, TGFβ, and IL-1β. Moreover, changes in fibrinogen levels observed in TSm rats suggested a potential role for these proteins in reducing/preventing TBI-induced coagulopathies. These data facilitate further investigations to identify specific pathways and proteins that may serve as key targets for the development of neuroprotective therapies.

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“…For the glutamate uptake assay, the treated astrocyte medium was discarded, and the cells were washed with D-Hank's solution. The cells were preincubated with 300 nM glutamate for 7 min, and glutamate uptake was terminated with ice-cold Hank's solution, followed by immediate analysis using a glutamate assay kit [40,41]. The level of intracellular glutamate was analyzed using a glutamate assay kit (colorimetric) according to the manufacturer's instructions.…”

Section: Coimmunoprecipitation (Co-ip) and Western Blottingmentioning

confidence: 99%

Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription

Hou

Huang

et al. 2020

PPAR Research

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Adenosine receptors A1 (A1AR) and A2a (A2aAR) play an important role in regulating glutamate uptake to avoid glutamate accumulation that causes excitotoxicity in the brain; however, the precise mechanism of the effects of A1AR and A2aAR is unclear. Herein, we report that expression of the A1AR protein in the astrocyte membrane and the level of intracellular glutamate were decreased, while expression of the A2aR protein was elevated in cells exposed to oxygen-glucose deprivation (OGD) conditions. Coimmunoprecipitation (Co-IP) experiments showed that A1AR interacts with A2aAR under OGD conditions. The activation of A1AR and inactivation of A2aAR by 2-chloro-N6-cyclopentyladenosine (CCPA) and SCH58251, respectively, partly reversed OGD-mediated glutamate uptake dysfunction, elevated EAAT2, and PPARγ protein levels, and suppressed the expression of Ying Yang 1 (YY1). Both the silencing of YY1 and the activation of PPARγ upregulated EAAT2 expression. Moreover, YY1 silencing elevated the PPARγ level under both normal and OGD conditions. Histone deacetylase (HDAC)1 was found to interact with YY1, and HDAC1 silencing improved PPARγ promoter activity. Taken together, our findings suggest that A1AR-A2aAR heteromers regulate EAAT2 expression and glutamate uptake through the YY1-mediated recruitment of HDAC1 to the PPARγ promoter region.

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Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain

Cited by 9 publications

References 34 publications

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis

Potential Neuroprotective Mechanisms of Methamphetamine Treatment in Traumatic Brain Injury Defined by Large-Scale IonStar-Based Quantitative Proteomics

Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription

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