Plasma metabolomics profiles in rats with acute traumatic brain injury

Zheng, Fei; Xia, Zian; Zeng, Yifu; Luo, Jiayou; Peng, Sun; Cui, Hanjin; Wang, Yang; Tang, Tao; Zhou, Yunfei

doi:10.1371/journal.pone.0182025

Cited by 22 publications

(17 citation statements)

References 78 publications

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“…TRPV4 is also activated by 5', 6'-epoxyeicosatrienoic acid [44], which is a signaling molecule formed in various cell types via metabolism of arachidonic acid. Arachidonic acid is upregulated in the brain in response to traumatic brain injury [47]. OPCs proliferate in response to CNS injury [28], and this may be mediated by stimulation of TRPV4 via arachidonic acid metabolites during brain inflammation.…”

Section: Discussionmentioning

confidence: 99%

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation

Ohashi

Deyashiki

Miyake

et al. 2018

Pflugers Arch - Eur J Physiol

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Oligodendrocytes, which differentiate from oligodendrocyte precursor cells (OPCs), ensheath axons with myelin, play an essential role in rapid conduction of action potentials and metabolically support neurons. Elucidation of the mechanisms underlying the proliferation, migration, differentiation, and survival of OPCs is considered indispensable for determining the causes of central nervous system diseases. However, the relationship between these functions of OPCs and their intracellular Ca signaling has not been fully elucidated. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a Ca-permeable channel that responds to hypo-osmolarity, mild temperature, mechanical stimulation, and endogenous arachidonic acid metabolites, in OPCs. Trpv4 mRNA was detected in OPCs in vivo and in primary cultured rat OPCs. In Ca imaging experiments, treatment with the selective TRPV4 agonist GSK1016790A induced sustained elevation of the intracellular Ca concentration in OPCs in a concentration-dependent manner, which was almost completely suppressed by co-treatment with the selective TRPV4 antagonist HC067047. Stimulation of TRPV4 by GSK1016790A augmented OPC proliferation, which was abolished by co-treatment with HC067047, the intracellular Ca chelator BAPTA-AM, and the protein kinase C inhibitor bisindolylmaleimide II. By contrast, GSK1016790A did not significantly affect the migration or differentiation of OPCs. Taken together, these results suggest that TRPV4 is functionally expressed in OPCs and increases the proliferation of these cells without affecting their ability to differentiate into oligodendrocytes.

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Section: Discussionmentioning

confidence: 99%

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation

Ohashi

Deyashiki

Miyake

et al. 2018

Pflugers Arch - Eur J Physiol

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“…metabolism, amino acid metabolism, galactose metabolism, and arachidonic acid metabolism were disturbed in the plasma of rats subjected to TBI 18 . Another study revealed a decrease of citrate and aconitate in TBI patients' plasma amongst other disturbed metabolites 17 .…”

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confidence: 95%

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Rashad

Saigusa

Yamazaki

et al. 2020

Sci Rep

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Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.Metabolomics is the study of metabolite composition of cells, tissues or biological fluids. Recent technological advances in this field has allowed the discovery of new biomarkers of diseases such as coronary artery disease, septic shock and brain tumors as well as the discovery of new drugs 1-5 . Metabolomic analysis has also deepened our understanding of several disease models, leading to the discovery of new pathways or targets for drug therapies that could later be applied to the treatment of various diseases [6][7][8][9][10][11] . Indeed, metabolomics are closer to the phenotype of a given disease compared with transcriptomic or proteomic analysis, both of which are prone to downstream modifications and changes in activities 1,12 .Several techniques, tools and software platforms exist to study metabolomics, all of which complement each other 13 . The application of these tools has greatly enhanced our understanding of the pathophysiology of diseases in almost every field of research 14 . In the field of neuroscience, metabolomic analysis is used to study stroke 15 , brain tumors 16 , traumatic brain injury (TBI) 17,18 , neurodegenerative diseases 19 , hypoxic-ischemic encephalopathy 20 and depression 21 to name a few 22 . The application of metabolomic tools to study brain diseases have greatly enhanced our understanding of different pathologies, for example; we demonstrated the upregulation of the ceramide "Cer(d18:0/18:0)" and phosphocreatine following transient ischemia-reperfusion in mice using a mass spectrometric imaging approach 15 . Several studies have highlighted an array of small molecules, amino acids and lipids that were linked to stroke severity, progression or post-stroke cognitive deficits [23][...

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“…Metabolomic studies provide comprehensive information on various in vivo enzymatic activities and have been successfully applied to obtain disease markers in neurodegenerative pathologies. TBI metabolomic marker characterization have been performed using Nuclear Magnetic Resonance (NMR) (Bahado-Singh, 2016b; Glenn et al, 2013; Robertson et al, 2013; Viant et al, 2005), or Mass Spectrometry (MS) of lipids (Emmerich et al, 2016; Emmerich et al, 2017; Sheth et al, 2015), targeting smaller and specific classes of metabolites or liquid chromatography/mass spectrometry (LCMS) based metabolomics, targeting broader biochemical changes (Bahado-Singh, 2016a; Daley, 2016; Oresic et al, 2016; Yi et al, 2016; Zheng et al, 2017). In order to target a wide range of metabolites in the developing brain, we performed LC-MS based brain tissue metabolomics in a preclinical rat model subjected to a fluid percussion TBI.…”

Section: Introductionmentioning

confidence: 99%

Early behavioral and metabolomic change after mild to moderate traumatic brain injury in the developing brain

Chitturi

Liu

Santhakumar

et al. 2018

Neurochemistry International

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Pathophysiology of developmental traumatic brain injury (TBI) is unique due to intrinsic differences in the developing brain. Energy metabolic studies of the brain during early development (P13 to P30) have indicated acute oxidative energy metabolic decreases below 24 h after TBI, which generally recovered by 48 h. However, marked neurodegeneration and altered neural functional connectivity have been observed at later stages into adolescence. As secondary neurodegeneration is most prominent during the first week after TBI in the rat model, we hypothesized that the subacute TBI-metabolome may contain predictive markers of neurodegeneration. Sham and TBI metabolomes were examined at 72 h after a mild to moderate intensity TBI in male Sprague-Dawley rats aged P31. Sensorimotor behavior was assessed at 24, 48 and 72 h after injury, followed by 72-hour postmortem brain removal for metabolomics using Liquid Chromatography/Mass Spectrometry (LC-MS) measurement. Broad TBI-induced metabolomic shifts occurred with relatively higher intensity in the injury-lateralized (ipsilateral) hemisphere. Intensity of metabolomic perturbation correlated with the extent of sensorimotor behavioral deficit. N-acetyl-aspartate (NAA) levels at 72 h after TBI, predicted the extent of neurodegeneration assessed histochemically 7-days post TBI. Results from the multivariate untargeted approach clearly distinguished metabolomic shifts induced by TBI. Several pathways including amino acid, fatty acid and energy metabolism continued to be affected at 72 h after TBI, whose collective effects may determine the overall pathological response after TBI in early development including neurodegeneration.

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Plasma metabolomics profiles in rats with acute traumatic brain injury

Cited by 22 publications

References 78 publications

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Early behavioral and metabolomic change after mild to moderate traumatic brain injury in the developing brain

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