Dataset Information

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake.

ABSTRACT: Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2^-/-) mice exhibited an increase in cerebral interstitial glutamate and a reduction in glutamate uptake into astrocytes. The ability of NDRG2 to control EAAT-mediated glutamate uptake into astrocytes required NDRG2 to interact with and promote the function of Na⁺/K⁺-ATPase ?1, which could be disrupted by a Na⁺/K⁺-ATPase ?1 peptide. The deletion of NDRG2 or treatment with the Na⁺/K⁺-ATPase ?1 peptide significantly increased neuronal death upon a glutamate challenge and aggravated brain damage after ischemia. Our findings demonstrate that NDRG2 plays a pivotal role in promoting astroglial glutamate uptake from the interstitial space and protecting the brain from glutamate excitotoxicity.

SUBMITTER: Yin A

PROVIDER: S-EPMC7067740 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake.

Yin Anqi A Guo Hang H Tao Liang L Cai Guohong G Wang Yazhou Y Yao Libo L Xiong Lize L Zhang Jian J Li Yan Y

Translational stroke research 20190627 2

Glutamate is a prominent neurotransmitter responsible for excitatory synaptic transmission and is taken up by sodium-dependent excitatory amino acid transporters (EAATs) on astrocytes to maintain synaptic homeostasis. Here, we report that N-myc downstream regulated gene 2 (NDRG2), a known tumor suppressor, is required to facilitate astroglial glutamate uptake and protect the brain from glutamate excitotoxicity after ischemia. NDRG2 knockout (Ndrg2<sup>-/-</sup>) mice exhibited an increase in cer ...[more]

PMID: 31250377

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Project description:Abstract Background Brain metastases (BM) are the most frequent neoplasm in the central nervous system (CNS) and primary tumors frequently involved are melanoma, lung cancer and breast cancer. CNS localisation is associated with poor prognosis, and stereotactic radiosurgery (SRS) represents a treatment option for patients with a good performance status. Glutamate (Glu) is a neurotransmitter which plays a facilitating role in carcinogenesis and progression of malignant tumors, as well as in excitotoxicity. Glu efflux from the brain is regulated by scavengers glutamic oxaloacetic transaminase (GOT), glutamate-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH), with aspartate and lactate as catabolites. Glu efflux from the brain seems to be impaired in advanced-stage cancers, resulting in increased blood Glu levels where scavengers exert a protective role. Our hypothesis is that serum Glu and scavengers’ levels are related to neuroinvasion and treatment response in patients with BM and may represent potential biomarkers for BM course and prognosis. Material and Methods Serum Glu scavengers (GOT1, GPT and LDH), serum Glu, aspartate and lactate levels are collected in included patients treated and grouped in A) BM group of patients affected by BM from lung or breast cancer or melanoma, treated with SRS; B) Control-1 group of patients affected by lung cancer, breast cancer or melanoma but without BM and C) Control-2 group of patients with benign intracranial lesions (meningiomas, acoustic schwannomas) treated with SRS.In A) and C) serum metabolites and scavengers will be analyzed before and after SRS treatment (at 3, 6, 9 months) while in B) analyzed once. Blood levels in A) and C) help in identifying differences related to malignancy, the role of SRS and the association with disease control, while blood levels in A) and B) help in detecting differences related to BMs. Exclusion criteria are surgical or previous radiosurgical treatment for BM. This study has received Institutional Ethical Committee approval on 3rd August 2020 (Project NCH04-2020, Clinicaltrials.gov identifier: NCT04785521). Preliminary results Comparison between BM group (n = 32) and Control-1 (n=18) revealed a significant difference in LDH (271.93 vs 217.56 U/L; p 0.041) and lactate (1.86 vs 1.34 mmol/L, p = 0.022) and a trend towards significance in glutamate (103.43 vs 73.74 µmol/L, p = 0.07). Comparison between BM group (n=32) and Control-2 (n = 37) revealed a difference in LDH (271.93 vs 210.89 U/L; p < 0.001), lactate (1.86 vs 1.24 mmol/L; p < 0.001), aspartate (16.36 vs 10.22 µmol/L, p 0.006) and glutamate levels (123 vs 103 µmol/L, p = 0.052). Conclusion The present study is the first one addressing serum glutamate and scavenger levels in patients with BM. If the hypothesis will be confirmed, new targets in glutamate signalling pathway could be identified to define new therapeutic strategies in this challenging disease.

Dataset Information

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake.

Publications

NDRG2 Protects the Brain from Excitotoxicity by Facilitating Interstitial Glutamate Uptake.

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