Recombinant tissue plasminogen activator induces long-term anxiety-like behaviors via the ERK1/2-GAD1-GABA cascade in the hippocampus of a rat model

Dong, Mei-Xue; Li, Chenmeng; Shen, Peng; Hu, Qingchuan; Wei, You-Dong; Ren, Yifei; Yu, Jia; Gui, Siwen; Liu, Yiyun; Pan, Junxi; Xie, Peng

doi:10.1016/j.neuropharm.2017.09.039

Cited by 16 publications

(9 citation statements)

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“…The most significant integrated network in this study was “cellular compromise, lipid metabolism, and small molecule biochemistry,” with a total of 27 metabolites and 9 proteins involved. Those molecules in the network were recognized as the most relevant ones with depressive systems in patients with PD (Dong et al, 2017b ). We further performed ELISA tests for six differentially expressed proteins to identify some clinical biomarkers as an integral part of clinical researches (Mostafa et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…An orthogonal partial least squares-discriminant analysis (OPLS-DA) model was used to exhibit statistical differences and identify differentially expressed metabolites in patients with PDD relative to the other patients with PD, and this model was validated by a permutation test with 200 iterations. The differentially expressed metabolites were recognized with variable influence on projection values of greater than 1.0, fold change values of greater than ±1.5, and p -values (from Mann-Whitney U -tests) of less than 0.05 (Zheng et al, 2016 ; Dong et al, 2017b ). The classifications of differentially expressed metabolites were based on the HMDB database.…”

Section: Methodsmentioning

confidence: 99%

“…To explore the metabolic pathways associated with the differentially expressed metabolites and proteins, we used the commercially obtained Ingenuity Pathway Analysis software (IPA, QIAGEN, Düsseldorf, Germany) to annotate enriched molecular or cellular functions and to generate metabolite-protein integrated networks (Dong et al, 2017b ; Shen et al, 2017 ). We uploaded the lists and fold change values of differentially expressed metabolites and proteins onto the IPA software.…”

Section: Methodsmentioning

confidence: 99%

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Integrated Analysis Reveals Altered Lipid and Glucose Metabolism and Identifies NOTCH2 as a Biomarker for Parkinson's Disease Related Depression

Dong

Feng

et al. 2018

Front. Mol. Neurosci.

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Depression is a common comorbidity in Parkinson's disease (PD) but is underdiagnosed. We aim to investigate the altered metabolic pathways of Parkinson's disease-related depression (PDD) in plasma and to identify potential biomarkers for clinical diagnosis. Consecutive patients with PD were recruited, clinically assessed, and patients with PDD identified. Fasting plasma samples were collected from 99 patients and differentially expressed metabolites and proteins between patients with PDD and PD were identified using non-targeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and tandem mass tag (TMT)-based proteomics analysis, followed by an integrated analysis. Based on the above results, enzyme-linked immune sorbent assay (ELISA) tests were then performed to identify potential biomarkers for PDD. In clinics, patients with PDD suffered less hypertension and had lower serum low-density lipoprotein cholesterol and apolipoprotein B levels when compared to the other patients with PD. A total of 85 differentially expressed metabolites were identified in metabolomics analysis. These metabolites were mainly lipids and lipid-like molecules, involved in lipid and glucose metabolic pathways. According to proteomics analysis, 17 differentially expressed proteins were identified, and 12 metabolic pathways were enriched, which were predominantly related to glucose metabolism. Integrated analysis indicated that altered lipid and glucose metabolism in PDD may induce cellular injury through oxidative stress. Additionally, plasma levels of several proteins were confirmed to be significantly altered and correlated with depressive severity. NOTCH2 may be a potential blood biomarker for PDD, with an optimal cut-off point of 0.91 ng/ml, a sensitivity value of 95.65%, and a specificity value of 81.58%. Depressive symptoms are associated with lipid and glucose metabolism in patients with PD and NOTCH2 may be a potential blood biomarker for the clinical diagnosis of PDD.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Integrated Analysis Reveals Altered Lipid and Glucose Metabolism and Identifies NOTCH2 as a Biomarker for Parkinson's Disease Related Depression

Dong

Feng

et al. 2018

Front. Mol. Neurosci.

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“…The partial least squares-discriminant analysis (PLS-DA) model was constructed to show statistical differences and identify metabolites differentially expressed between PD patients and healthy controls, and this model was further validated by a permutation test with 200 iterations. Metabolites with variable influence on projection values (obtained from the PLS-DA model) of greater than 1.0, fold change values of greater than ±2, and p-values of less than 0.05 (Dong et al, 2018b) were identified to be differentially expressed. These differentially expressed metabolites were then classified by chemical taxonomy based on the HMDB database, and metabolic pathway analysis was further performed by MetaboAnalyst 4.0 3 (Chong et al, 2018).…”

Section: Metabolomics Analysismentioning

confidence: 99%

Integrated Metabolomics and Proteomics Analysis Reveals Plasma Lipid Metabolic Disturbance in Patients With Parkinson’s Disease

Dong

Huang

et al. 2020

Front. Mol. Neurosci.

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Parkinson's disease (PD) is a common neurodegenerative disease in the elderly with a pathogenesis that remains unclear. We aimed to explore its pathogenesis through plasma integrated metabolomics and proteomics analysis. The clinical data of consecutively recruited PD patients and healthy controls were assessed. Fasting plasma samples were obtained and analyzed using metabolomics and proteomics methods. After that, differentially expressed metabolites and proteins were identified for further bioinformatics analysis. No significant difference was found in the clinical data between these two groups. Eighty-three metabolites were differentially expressed in PD patients identified by metabolomics analysis. These metabolites were predominately lipid and lipid-like molecules (63%), among which 25% were sphingolipids. The sphingolipid metabolism pathway was enriched and tended to be activated in the following KEGG pathway analysis. According to the proteomics analysis, forty proteins were identified to be differentially expressed, seven of which were apolipoproteins. Furthermore, five of the six top ranking Gene Ontology terms from cellular components and eleven of the other fourteen Gene Ontology terms from biological processes were directly associated with lipid metabolism. In KEGG pathway analysis, the five enriched pathways were also significantly related with lipid metabolism (p < 0.05). Overall, Parkinson's disease is associated with plasma lipid metabolic disturbance, including an activated sphingolipid metabolism and decreased apolipoproteins.

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“…For instance, our previous studies indicated that rtPA can potentiate excitotoxic lesions and lead to neuronal death induced by NMDA, 3 as well as induce long-term anxiety-like behaviors via the ERK1/2-GAD1-GABA cascade. 4 Thus, more attention should be paid to the adverse neurological effects of rtPA to achieve more effective treatment of ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex

Chen

Bai

et al. 2018

NDT

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IntroductionAlthough recombinant tissue plasminogen activator (rtPA) is a widely used therapy in patients with acute ischemic stroke, rtPA-induced toxicity or its adverse effects have been reported in our previous studies. However, Ginkgo biloba extract (GBE) may provide neuroprotective effects against rtPA-induced toxicity. Thus, in the present study, we investigated whether a single administration of rtPA caused neurotoxicity in the prefrontal cortex (PFC) of rats and determined whether GBE or its diterpene ginkgolide (DG) constituents were neuroprotective against any rtPA-induced toxicity.Materials and methodsWe randomly divided adult Sprague-Dawley rats into four groups that were intravenously administered saline, rtPA, rtPA+DG, or rtPA+GBE. The rats were sacrificed 24 hours later and the whole brain removed. A gas chromatography–mass spectrometry metabolomic approach was used to detect molecular changes in the PFC among the groups. Multivariate statistical and pathway analyses were used to determine the relevant metabolites as well as their functions and pathways.ResultsWe found 32 metabolites differentially altered in the four groups that were primarily involved in neurotransmitter, amino acid, energy, lipid, and nucleotide metabolism. Our results indicated that a single rtPA administration caused metabolic disturbances in the PFC. Both GBE and DG effectively ameliorated these rtPA-induced disturbances, although DG better controlled the rtPA-induced glutamate and aspartate excitotoxicity and the activation of NMDA receptor.ConclusionOur results provide important novel mechanistic insights into the adverse effects of rtPA and offer directions for future exploration on the thrombolytic effects of rtPA combined with the administration of DG or GBE for the treatment of acute ischemic stroke in humans.

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Recombinant tissue plasminogen activator induces long-term anxiety-like behaviors via the ERK1/2-GAD1-GABA cascade in the hippocampus of a rat model

Cited by 16 publications

References 72 publications

Integrated Analysis Reveals Altered Lipid and Glucose Metabolism and Identifies NOTCH2 as a Biomarker for Parkinson's Disease Related Depression

Integrated Analysis Reveals Altered Lipid and Glucose Metabolism and Identifies NOTCH2 as a Biomarker for Parkinson's Disease Related Depression

Integrated Metabolomics and Proteomics Analysis Reveals Plasma Lipid Metabolic Disturbance in Patients With Parkinson’s Disease

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex

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