Skip to main content

Advertisement

SpringerLink
Log in

Systems biology in unruptured intracranial aneurysm: a metabolomics study in serum for the detection of biomarkers

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Intracranial aneurysm (IA) is a common devastating condition occurs in up to 6 % of the population. It is asymptomatic but potentially fatal because of the progressive enlargement and rupturing leads to subarachnoid hemorrhage. Early diagnosis of IA is more valuable before it ruptures and hemorrhage. The diagnosis of IA is usually carried out using computerized tomography or magnetic resonance imaging. However, there is no biochemical test or a marker available for diagnosis. Serum metabolites were analyzed from normal and unruptured intracranial aneurysms patients (UIA) by NMR spectroscopy to identify the presence of serum markers, which could provide a clue for diagnosis and altered metabolic pathways in UIA condition. Analysis of proton spectra revealed significant perturbations in 20 serum metabolites in UIA. Multivariate analysis showed a distinct separation of normal from UIA based on 17 most contributing metabolites, and the scoring algorithm determines the perturbed metabolic pathways in UIA (urea cycle, citric acid cycle and ammonia recycling). Also, the gene expression analysis shows the significant (p ≤ 0.05) change in ARG, CPS1 and OTC genes leading to dysregulation in the urea cycle. Further, estimation of urea showed a significant increase in serum urea, which provides the prospect of rapid diagnosis. Overall, this study demonstrates the promise of developing biomarkers for the diagnosis of UIA from serum. In addition, the implementation of systems biological approach in metabolomic context gained an understanding about UIA that reflects the numerous metabolic pathways identified to be affected in disease condition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahmed, S. S. J., & Ramakrishnan, V. (2012). Systems biological approach of molecular descriptors connectivity: Optimal descriptors for oral bioavailability prediction. PLoS ONE, 7(7), e40654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmed, S. S., Santosh, W., Kumar, S., & Christlet, H. T. (2009). Metabolic profiling of parkinson’s disease: Evidence of biomarker from gene expression analysis and rapid neural network detection. Journal of Biomedical Science, 16, 63.

    Article  PubMed  PubMed Central  Google Scholar 

  • Alekseenko, A. V., Lemeshchenko, V. V., Pekun, T. G., Waseem, T. V., & Fedorovich, S. V. (2012). Glutamate-induced free radical formation in rat brain synaptosomes is not dependent on intrasynaptosomal mitochondria membrane potential. Neuroscience Letters, 513, 238–242.

    Article  CAS  PubMed  Google Scholar 

  • Altaf-Ul-Amin, M., Shinbo, Y., Mihara, K., Kurokawa, K., & Kanaya, S. (2006). Development and implementation of an algorithm for detection of protein complexes in large interaction networks. BMC Bioinformatics, 14(7), 207.

    Article  Google Scholar 

  • Austin, G., Fisher, S., Dickson, D., Anderson, D., & Richardson, S. (1993). The significance of the extracellular matrix in intracranial aneurysms. Annals of Clinical and Laboratory Science, 23, 97–105.

    CAS  PubMed  Google Scholar 

  • Barrett, T., Wilhite, S., Ledoux, P., et al. (2013). NCBI GEO: Archive for functional genomics data sets–update. Nucleic Acids Research, 41, D991–D995.

    Article  CAS  PubMed  Google Scholar 

  • Caranci, F., Briganti, F., Cirillo, L., Leonardi, M., and Muto, M. (2013) Epidemiology and genetics of intracranial aneurysms. Eur J Radiol. pii: S0720-048X(13)00011-9.

  • Chalouhi, N., Ali, M. S., Jabbour, P. M., et al. (2012a). Biology of intracranial aneurysms: Role of inflammation. Journal of Cerebral Blood Flow and Metabolism, 32, 1659–1676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chalouhi, N., Ali, M. S., Starke, R. M., et al. (2012b). Cigarette smoke and inflammation: Role in cerebral aneurysm formation and rupture. Mediators of Inflammation, 2012, 271582.

    Article  PubMed  PubMed Central  Google Scholar 

  • Crawley, F., Clifton, A., & Brown, M. M. (1999). Should we screen for familial intracranial aneurysm? Stroke, 30, 312–316.

    Article  CAS  PubMed  Google Scholar 

  • Diana, R. W., Elizabeth, J., Joseph, P., et al. (2010). Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells. Journal of Biological Chemistry, 285, 30516–30522.

    Article  Google Scholar 

  • Donald, R. W., Di John, G., & Vincent, J. P. (1971). Manual and automated methods for urea nitrogen measurement in whole serum. Clinical Chemistry, 17, 891–895.

    Google Scholar 

  • Douglas, C., & Isabel, L. (1997). Gelatinase activity and the occurrence of cerebral aneurysms. Stroke, 28, 799–804.

    Article  Google Scholar 

  • Dunne, V. G., Bhattachayya, S., Besser, M., Rae, C., & Griffin, J. L. (2005). Metabolites from cerebrospinal fluid in aneurysmal subarachnoid haemorrhage correlate with vasospasm and clinical outcome: A pattern-recognition 1H NMR study. NMR in Biomedicine, 18, 24–33.

    Article  CAS  PubMed  Google Scholar 

  • Fisher, M., & Zito, J. L. (1983). Focal cerebral ischemia distal to a cerebral aneurysm in hereditary hemorrhagic telangiectasia. Stroke, 14, 419–421.

    Article  CAS  PubMed  Google Scholar 

  • Frolkis, A., Knox, C., Lim, E., et al. (2010). SMPDB: The small molecule pathway database. Nucleic Acids Research, 38, D480–D487.

    Article  CAS  PubMed  Google Scholar 

  • Fukushima, A., Kusano, M., Redestig, H., Arita, M., and Saito K. (2011) Metabolomic correlation-network modules in Arabidopsis based on a graph-clustering approach. BMC Syst Biol.1;5:1.

  • Glantz, L., Nates, J. L., Trembovler, V., Bass, R., & Shohami, E. (1996). Polyamines induce blood-brain barrier disruption and edema formation in the rat. Journal of Basic and Clinical Physiology and Pharmacology, 7, 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Helbok, R., Ko, S. B., Schmidt, J. M., et al. (2011). Global cerebral edema and brain metabolism after subarachnoid hemorrhage. Stroke, 42, 1534–1539.

    Article  PubMed  Google Scholar 

  • Joanna, P., Michal, K., Tadeusz, K., et al. (2010). Gene expression profiles in human ruptured and unruptured intracranial aneurysms: What is the role of inflammation? Stroke, 41, 224–231.

    Article  Google Scholar 

  • Jung, J. Y., Lee, H. S., Kang, D. G., et al. (2011). 1H-NMR-based metabolomics study of cerebral infarction. Stroke, 42, 1282–1288.

    Article  CAS  PubMed  Google Scholar 

  • Kett-White, R., Hutchinson, P. J., al-Rawi, P. G., et al. (2002). Extracellular lactate/pyruvate and glutamate changes in patients during per-operative episodes of cerebral ischaemia. Acta Neurochirurgica Supplementum, 81, 363–365.

    CAS  Google Scholar 

  • Li, L., Yang, X., Jiang, F., Dusting, G. J., & Wu, Z. (2010). Transcriptome-wide characterization of gene expression associated with unruptured intracranial aneurysms. European Neurology, 62, 330–337.

    Article  CAS  Google Scholar 

  • Lotfi, H. B., & James, M. P. (2011). Current imaging assessment and treatment of intracranial aneurysms. American Journal of Roentgenol, 196, 132–144.

    Article  Google Scholar 

  • Lu, G., Huang, L., Zhang, X. L., et al. (2011). Geng influence of hemodynamic factors on rupture of intracranial aneurysms: Patient-specific 3D mirror aneurysms model computational fluid dynamics simulation. American Journal of Neuroradiology, 32, 1255–1261.

    Article  CAS  PubMed  Google Scholar 

  • Marchese, E., Vignati, A., Albanese, A., et al. (2010). Comparative evaluation of genome-wide gene expression profiles in ruptured and unruptured human intracranial aneurysms. Journal of Biological Regulators and Homeostatic Agents, 24, 185–195.

    CAS  PubMed  Google Scholar 

  • Massieu, L., Gómez-Román, N., & Montiel, T. (2000). In vivo potentiation of glutamate-mediated neuronal damage after chronic administration of the glycolysis inhibitor iodoacetate. Experimental Neurology, 165, 257–267.

    Article  CAS  PubMed  Google Scholar 

  • Mori, K., Nakajima, K., & Maeda, M. (1993). Long-term monitoring of CSF lactate levels and lactate/pyruvate ratios following subarachnoid haemorrhage. Acta Neurochir (Wien), 125, 20–26.

    Article  CAS  Google Scholar 

  • Muralikrishna, R., James, F. H., & Robert, J. D. (1999). Polyamine response to CNS injury: for better or for worse? Recent Research Developments in Neurochemistry, 2, 517–532.

    Google Scholar 

  • Neil-Dwyer, G., Bartlett, J. R., Nicholls, A. C., Narcisi, P., & Pope, F. M. (1983). Collagen deficiency and ruptured cerebral aneurysms. A clinical and biochemical study. Journal of Neurosurgery, 59, 16–20.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson, O. G., Säveland, H., Boris-Möller, F., Brandt, L., & Wieloch, T. (1996). Increased levels of glutamate in patients with subarachnoid haemorrhage as measured by intracerebral microdialysis. Acta Neurochirurgica Supplementum, 67, 45–47.

    CAS  Google Scholar 

  • Nishiumi, S., Kobayashi, T., Ikeda, A., et al. (2012). A novel serum metabolomics-based diagnostic approach for colorectal cancer. PLoS ONE, 7(7), e40459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohsawa, N. (1990). Recent progress in polyamine research. Human Cell, 3, 91–98.

    CAS  PubMed  Google Scholar 

  • Parfenova, H., Basuroy, S., Bhattacharya, S., et al. (2006). Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: Contributions of HO-1 and HO-2 to cytoprotection. American Journal of Physiology Cell Physiology, 290, 1399–1410.

    Article  Google Scholar 

  • Parfenova, H., Carratu, P., Tcheranova, D., Fedinec, A., Pourcyrous, M., & Leffler, C. W. (2005). Epileptic seizures cause extended postictal cerebral vascular dysfunction that is prevented by HO-1 overexpression. American Journal of Physiology: Heart and Circulatory Physiology, 288, H2843–H2850.

    CAS  PubMed  Google Scholar 

  • Pentimalli, L., Modesti, A., Vignati, A., et al. (2004). Role of apoptosis in intracranial aneurysm rupture. Journal of Neurosurgery, 101, 1018–1025.

    Article  PubMed  Google Scholar 

  • Pisapia, J. M., Wendell, L. C., Kumar, M. A., Zager, E. L., & Levine, J. M. (2011). Lactate-to-pyruvate ratio as a marker of propofol infusion syndrome after subarachnoid hemorrhage Neurocrit Care, 15, 134–138.

    CAS  PubMed  Google Scholar 

  • Psychogios, N., Hau, D. D., Peng, J., et al. (2011). The human serum metabolome. PLoS ONE, 6(2), e16957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reynolds, I. J., & Hastings, T. G. (1995). Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. Journal of Neuroscience, 5, 3318–3327.

    Google Scholar 

  • Roder, C., Kasuya, H., Harati, A., Tatagiba, M., Inoue, I., & Krischek, B. (2012). Meta-analysis of microarray gene expression studies on intracranial aneurysms. Neuroscience, 201, 105–113.

    Article  CAS  PubMed  Google Scholar 

  • Rupérez, F. J., Ramos-Mozo, P., Teul, J., Martinez-Pinna, R., Garcia, A., Malet-Martino, M., et al. (2012). Metabolomic study of plasma of patients with abdominal aortic aneurysm. Analytical and Bioanalytical Chemistry, 403, 1651–1660.

    Article  PubMed  Google Scholar 

  • Säveland, H., Nilsson, O. G., Boris-Möller, F., Wieloch, T., & Brandt, L. (1996). Intracerebral microdialysis of glutamate and aspartate in two vascular territories after aneurysmal subarachnoid hemorrhage. Neurosurgery, 38, 12–19.

    Article  PubMed  Google Scholar 

  • Shah, S. H., Sun, J. L., Stevens, R. D., et al. (2012). Baseline metabolomic profiles predict cardiovascular events in patients at risk for coronary artery disease. American Heart Journal, 163, 844–850.

    Article  CAS  PubMed  Google Scholar 

  • Southerland, A. M., Meschia, J. F., & Worrall, B. B. (2013). Shared associations of nonatherosclerotic, large-vessel, cerebrovascular arteriopathies: considering intracranial aneurysms, cervical artery dissection, moyamoya disease and fibromuscular dysplasia. Current Opinion in Neurology, 26, 13–28.

    Article  PubMed  Google Scholar 

  • Tulamo, R., Frösen, J., Laaksamo, E., Niemelä, M., Laakso, A., & Hernesniemi, J. (2011). Why does the cerebral artery aneurysm rupture? Duodecim, 127, 244–252.

    PubMed  Google Scholar 

  • Yao, H., Matsumoto, T., Hirano, M., et al. (1990). Striatal glutamic acid and gamma-aminobutyric acid in transient cerebral ischemia in spontaneously hypertensive rats. Japanese Heart Journal, 31, 385–392.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The author wishes to thanks Drs. R. Murugasan, R. Pitchappan (CHRI) for their intellectual input and Dr. Suresh Kumar (SRM), for his opinion in selecting the patients for this study.

Conflict of interest

The author has no conflict of interest relevant to this study.

Author information

Authors and Affiliations

  1. Department of Computational Biology, Chettinad Hospital and Research Institute, Kelambakkam, 603 103, Tamil Nadu, India

    Shiek S. S. J. Ahmed

  2. Department of Biotechnology, SRM University, Kattankulathur, 603 203, Tamil Nadu, India

    Shiek S. S. J. Ahmed

Authors
  1. Shiek S. S. J. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiek S. S. J. Ahmed.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmed, S.S.S.J. Systems biology in unruptured intracranial aneurysm: a metabolomics study in serum for the detection of biomarkers. Metabolomics 10, 52–62 (2014). https://doi.org/10.1007/s11306-013-0551-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-013-0551-8

Keywords

Search

Navigation