Abstract

Metabolites, as essential biochemical molecules, play a critical role in brain metabolism and neurological health. They contribute to energy production, neurotransmitter synthesis, and cellular signaling, making them integral to normal brain function. Dysregulation of metabolites is a hallmark of various neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Impairments in glucose metabolism, oxidative stress, and neurotransmitter imbalances significantly impact neuronal function and disease progression. Emerging research in metabolomics has enabled the identification of disease specific biomarkers, providing insights into early diagnosis and potential therapeutic interventions. Additionally, the gut brain axis has been recognized as a key regulator of neurochemical processes, further emphasizing the systemic nature of metabolic influences on neurological health. Advances in metabolite based therapeutics, such as targeted metabolic modulation and antioxidant strategies, offer promising avenues for treating neurodegenerative and psychiatric disorders. Despite the complexity of metabolomic data, integrating multi-omics approaches and artificial intelligence driven analytics holds great potential for personalized medicine in neurology. This review explores the role of metabolites in brain function, their involvement in neurological diseases, and the future directions of metabolomics in clinical applications.

• 1.   Nicholson J.K., Lindon J.C., Holmes E. “Metabonomics”: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica Fate Foreign Compd Biol Syst. 1999 Nov; 29(11): 1181–9.
• 2.   Patti G.J., Yanes O., Siuzdak G. Metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol. 2012 Apr; 13(4): 263–9.
• 3.   Johnson C.H., Ivanisevic J., Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016 Jul; 17(7): 451–9.
• 4.   Kaddurah-Daouk R., Krishnan K.R.R. Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2009 Jan; 34(1): 173–86.
• 5.   Butterfield D.A., Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019 Mar; 20(3): 148–60.
• 6.   Zheng C., Shao W., Chen X., Zhang B., Wang G., Zhang W. Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis. Int J Infect Dis IJID Off Publ Int
• 7.   Lewén A., Matz P., Chan P.H. Free radical pathways in CNS injury. J Neurotrauma. 2000 Oct; 17(10): 871–90
• 8.   Moffett J.R., Ross B., Arun P., Madhavarao C.N., Namboodiri AMA. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol. 2007 Feb; 81(2): 89–131.
• 9.   Morais L.H., Schreiber H.L., Mazmanian S.K. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol. 2021 Apr; 19(4): 241–55.
• 10.   Harris J.J., Jolivet R., Attwell D. Synaptic energy use and supply. Neuron. 2012 Sep 6; 75(5): 762–77.
• 11.   Cunnane S.C., Trushina E., Morland C., Prigione A., Casadesus G., Andrews Z.B., et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of
• 12.   Berk M., Williams L.J., Jacka F.N., O’Neil A., Pasco J.A., Moylan S., et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep
• 13.   Ferreira-Vieira T.H., Guimaraes I.M., Silva F.R., Ribeiro F.M. Alzheimer’s disease: Targeting the Cholinergic System. Curr Neuropharmacol. 2016; 14(1): 101–15.
• 14.   Chen Y., Yao H., Zhang N., Wu J., Gao S., Guo J., et al. Proteomic Analysis Identifies Prolonged Disturbances in Pathways Related to Cholesterol Metabolism and Myocardium Function in the COVID-19 Recovery Stage. J Proteome Res. 2021 Jul 2; 20(7): 3463–74.
• 15.   Martín M.G., Pfrieger F., Dotti C.G. Cholesterol in brain disease: sometimes determinant and frequently implicated. EMBO Rep. 2014 Oct; 15(10):1 036–52.
• 16.   Chen Z., Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol. 2013
• 17.   Kapogiannis D., Avgerinos K.I. Brain glucose and ketone utilization in brain aging and neurodegenerative diseases. Int Rev Neurobiol. 2020; 154: 79–110.
• 18.   Sian-Hülsmann J., Mandel S., Youdim MBH, Riederer P. The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem. 2011 Sep; 118(6): 939–57.
• 19.   Dong X. xia, Wang Y., Qin Z. hong. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009 Apr; 30(4): 379– 87.
• 20.   Lassmann H. Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease. J Neural Transm Vienna Austria 1996. 2011 May; 118(5): 747–52.
• 21.   Baillet A., Chanteperdrix V., Trocmé C., Casez P., Garrel C., Besson G. The role of oxidative stress in amyotrophic lateral sclerosis and Parkinson’s disease. Neurochem Res. 2010 Oct;
• 22.   Stone T.W., Darlington L.G. The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol. 2013 Jul; 169(6): 1211–27.
• 23.   Angelova P.R., Abramov A.Y. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Lett. 2018 Mar; 592(5): 692–702.
• 24.   Gandhi S., Abramov A.Y. Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev. 2012;2012:428010.
• 25.   Praticò D. Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci. 2008 Dec;29(12):609–15.
• 26.   Blesa J., Trigo-Damas I., Quiroga-Varela A., Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat. 2015; 9: 91.
• 27.   Robberecht W. Oxidative stress in amyotrophic lateral sclerosis. J Neurol. 2000 Mar; 247 Suppl 1: I1-6.
• 28.   Fischer M.T., Sharma R., Lim J.L., Haider L., Frischer J.M., Drexhage J., et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage
• 29.   Mancuso M., Orsucci D.., Volpi L., Calsolaro V, Siciliano G. Coenzyme Q10 in neuromuscular and neurodegenerative disorders. Curr Drug Targets. 2010 Jan;11(1):111–21.
• 30.   Carabotti M., Scirocco A., Maselli M.A., Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015; 28(2): 203–9.
• 31.   Blaut M., Clavel T. Metabolic diversity of the intestinal microbiota: implications for health and disease. J Nutr. 2007 Mar; 137(3 Suppl 2): 751S-5S.
• 32.   Date Y., Kojima M., Hosoda H., Sawaguchi A, Mondal M.S., Suganuma T., et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000 Nov; 141(11): 4255–61.
• 33.   Holst J.J. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct; 87(4): 1409– 39.
• 34.   Turnbaugh P.J., Ley R.E., Mahowald MA, Magrini V., Mardis E.R., Gordon J.I. An obesityassociated gut microbiome with increased capacity for energy harvest. Nature. 2006 Dec;
• 35.   Sudo N., Chida Y., Aiba Y., Sonoda J., Oyama N., Yu X.N., et al. Postnatal microbial colonization programs the hypothalamicpituitary-adrenal system for stress response in
• 36.   Ridaura V.K., Faith J.J., Rey F.E., Cheng J., Duncan A.E., Kau A.L., et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013 Sep 6;
• 37.   Del Prete E., Beatino M.F., Campese N., Giampietri L., Siciliano G., Ceravolo R., et al. Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach. J
• 38.   Hampel H., Frank R., Broich K., Teipel S.J., Katz R.G., Hardy J, et al. Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov. 2010 Jul;

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Funding