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NMR based Serum metabolomics revealed metabolic signatures associated with oxidative stress and mitochondrial damage in brain stroke

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Abstract

Brain stroke (BS, also known as a cerebrovascular accident), represents a serious global health crisis. It has been a leading cause of permanent disability and unfortunately, frequent fatalities due to lack of timely medical intervention. While progress has been made in prevention and management, the complexities and consequences of stroke continue to pose significant challenges, especially, its impact on patient’s quality of life and independence. During stroke, there is a substantial decrease in oxygen supply to the brain leading to alteration of cellular metabolic pathways, including those involved in mitochondrial-damage, leading to mitochondrial-dysfunction. The present proof-of-the-concept metabolomics study has been performed to gain insights into the metabolic pathways altered following a brain stroke and discover new potential targets for timely interventions to mitigate the effects of cellular and mitochondrial damage in BS. The serum metabolic profiles of 108 BS-patients were measured using 800 MHz NMR spectroscopy and compared with 60 age and sex matched normal control (NC) subjects. Compared to NC, the serum levels of glutamate, TCA-cycle intermediates (such as citrate, succinate, etc.), and membrane metabolites (betaine, choline, etc.) were found to be decreased BS patients, whereas those of methionine, mannose, mannitol, phenylalanine, urea, creatine and organic acids (such as 3-hydroxybutyrate and acetone) were found to be elevated in BS patients. These metabolic changes hinted towards hypoxia mediated mitochondrial dysfunction in BS-patients. Further, the area under receiver operating characteristic curve (ROC) values for five metabolic features (methionine, mannitol, phenylalanine, mannose and urea) found to be more than 0.9 suggesting their high sensitivity and specificity for differentiating BS from NC subjects.

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Data availability

The manuscript contains all the relevant data with its supporting information files. The corresponding authors will be provided with raw NMR spectral data upon request. The raw NMR data has been uploaded on public repository ZENODO (Accession Number: 7792273 | https://doi.org/10.5281/zenodo.7046041).

Abbreviations

NMR :

Nuclear Magnetic Resonance

BS :

Brain Stroke

IS :

Ischemic stroke

MRI :

Magnetic Resonance Imaging

CVD :

Cardiovascular disease

CPMG :

Carr–Purcell–Meiboom–Gill

BCAA :

Branched‐chain amino acid

BTR :

Branched chain amino acids-to-tyrosine ratio

PTR :

Phenylalanine-to-Tyrosine ratio

HTR :

Histidine-to-Tyrosine ratio

CI :

Confidence interval

ICU :

Intensive care unit

3-HB :

3-Hydroxy-isobutyrate

TSP :

Trimethylsilylpropionic acid

NAG :

N-acetyl glycoprotein

FDA :

Food and Drug Administration

MHz :

Megahertz

NC :

Normal control

HS :

Hemorrhagic stroke

ICH :

Intracerebral hemorrhage

PLS-DA :

Partial least square-discriminant analysis

PCA :

Principal component analysis

MDA :

Mean decrease accuracy

RF :

Random forest

ROC :

Receiver operating characteristic

AUROC :

Area under ROC curve

ESM :

Electronic Supplementary Material

1D/2D :

One/Two dimensional

CT :

Computerized tomography

LDL :

Low-density lipoproteins

VLDL :

Very Low-density lipoproteins

HDL :

High density lipoprotein

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Acknowledgements

Authors would like to acknowledge the Department of Medical Education, Govt. of Uttar Pradesh for supporting the High Field NMR Facility at Centre of Biomedical Research, Lucknow, India. AK acknowledges the financial assistance from Department of Science and Technology, Govt of India support scheme DST/CSRI/PDF-63/2018 under Cognitive Science Research Initiative program. GS acknowledges receipt of the JRF fellowship from The CSIR, New Delhi, India. The manuscript communication number received from Integral University is IU/R&D/2023-MCN0002286.

Funding

(1). Intramural funding from the Centre of Biomedical Research (CBMR), Lucknow (Project No. CBMR/ IMR/0010/2021 | PI: Dr. Dinesh Kumar). (2). Department of Science and Technology, Govt of India support scheme DST/CSRI/PDF-63/2018 under Cognitive Science Research Initiative program. (3). Department of Science and Technology for financial assistance under SERB EMR Scheme (Ref. No.: EMR/2016/001756). (4). Council of Scientific and Industrial Research (CSIR), New Delhi, India.

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Authors and Affiliations

  1. Department of Chemistry, Integral University, Lucknow, 226026, India

    Sachin Yadav & Abdul Rahman Khan

  2. Department of Botany, Deen Dayal Upadhyaya Gorakhpur University, Gorakhpur, 273009, Uttar Pradesh, India

    Abhai Kumar

  3. Department of Zoology, Dayal Upadhyaya Gorakhpur University, Gorakhpur, 273009, Uttar Pradesh, India

    Smita Singh

  4. Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India

    Shahnawaz Ahmad & Rameshwar Nath Chaurasia

  5. Centre of Biomedical Research (CBMR), SGPGIMS Campus, Lucknow, 226014, Uttar Pradesh, India

    Gurvinder Singh & Dinesh Kumar

  6. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India

    Gurvinder Singh

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Contributions

DK and AK: Conceptualization of idea and study design.

RNC: Involved in the clinical screening of patients, imaging analysis and clinical data collection.

AK, SS and SA: Collection of blood samples, extraction of serum and compiling the clinical and demographic details.

SY and GS: Prepared NMR buffer and NMR samples, recorded the NMR spectra and performed the concentration profiling.

ARK: Manuscript proof reading, review, and submission.

DK and SY: Analyzed the metabolomics data, prepared the figures, and drafted the manuscript.

Corresponding authors

Correspondence to Abhai Kumar, Rameshwar Nath Chaurasia or Dinesh Kumar.

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Yadav, S., Kumar, A., Singh, S. et al. NMR based Serum metabolomics revealed metabolic signatures associated with oxidative stress and mitochondrial damage in brain stroke. Metab Brain Dis 39, 283–294 (2024). https://doi.org/10.1007/s11011-023-01331-2

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