Abstract
Acute cold stress may trigger systemic biochemical and physiological changes in the living organisms, which leads to rapid loss of homeostasis. These changes may reverse due to self-regulatory mechanism of the organism or by the intervention of suitable medication in the form of herbs. The present study was undertaken to assess the alterations in metabolites levels arising due to acute cold stress and to monitor the restoration of these changes by suitable herb intervention. Male Sprague-Dawley rats were exposed to acute cold stress of −10°C for 3 h and urine samples were collected and analyzed by NMR spectroscopy in conjugation with Principal Component Analysis (PCA). The study revealed highly significant biochemical changes in urinary metabolites and also demonstrated the protective effects of Tinospora Cordifolia (Tc) extract on the stressed rats. These changes suggest the involvement of various metabolic pathways such as Tricarboxylic Acid (TCA) cycle, gut microbiota, renal function, catecholamines and muscle metabolism in the metabolic alterations induced by cold stress and the compensation required to restore homeostasis. The present study forms the basis of future studies to establish potential biomarkers for cold stress in humans and lay down the optimum dosage of Tc to be administered for providing immunity to the body as prophylactic and mitigating agent against environmental insult such as cold stress.
Similar content being viewed by others
Abbreviations
- NMR:
-
Nuclear magnetic resonance
- PCA:
-
Principal component analysis
- SD:
-
Sprague-Dawley
- TCA:
-
Tricarboxylic acid cycle
- TSP:
-
3-(Trimethylsilyl) propionic-2, 2, 3, 3-d4 acid sodium salt
- GIT:
-
Gastrointestinal tract
- SNS:
-
Sympathetic nervous system
References
Bishayi, B., Roychowdhury, S., & Ghosh, S. (2002). Hepatoprotective and immunomodulatory properties of Tinospora Cordifolia in CCl4 intoxicated mature albino rats. Journal of Toxicological Science, 27, 139–146.
Blomstrand, E., & Newsholme, E. A. (1992). Effect of branched-chain amino acid supplementation on the exercise-induced change in aromatic amino acid concentration in human muscle. Acta Physiologica Scandinavica, 146(3), 293–298.
Bollard, M. E., Stanley, E. G., Lindon, J. C., Nicholson, J. K., & Holmes, E. (2005). NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition. NMR Biomedicine, 18, 143–162.
Brindle, J. T., Antti, H., Holmes, E., Tranter, G., et al. (2002). Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H NMR- based metabonomics. Nature Medicine, 8, 1439–1444.
Cheng, X., & Su, H. (2010). Effects of climatic temperature stress on cardiovascular diseases. European Journal of Internal Medicine, 21, 164–167.
Dhabhar, F. S., McEwen, B. S., & Spencer, R. L. (1997). Adaptation to prolonged or repeated stress-comparison between rat strains showing intrinsic differences in reactivity to acute stress. Neuroendocrinology, 65, 360–368.
Dumas, M. E., Barton, R. H., Toye, A., et al. (2006). Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proceeding of National Academy of Sciences, 103, 12511–12516.
Epel, E. S. (2009). Psychological and metabolic stress: A recipe for accelerated cellular aging? Hormones, 8, 7–22.
Fedyk, M., Velykyi, M. M., Zababurina, M. L., & Oliiarnyk, O. D. (1996). The dynamic biosynthesis of nicotinamide coenzymes from nicotinamide and nicotinic acid in rat tissues. Ukrainskii Biokhimicheskii Zhurnal, 68(2), 29–33.
Gibala, M. J., Tarnopolsky, M. A., & Graham, T. E. (1997). Tricarboxylic acid cycle intermediates in human muscle at rest and during prolonged cycling. American Journal of Physiology, 272, E239–E244.
Goel, H. C., Prasad, J., & Singh, S. (2004). Radioprotective potential of an herbal extract of Tinospora cordifolia. Journal of Radiation Research (Tokyo), 45, 61–68.
Hawrelak, J. A., & Myers, S. P. (2004). The causes of intestinal dysbiosis: A review. Alternative Medicine Review, 9, 180–197.
Holmes, E., Bonner, F. W., & Nicholson, J. K. (1997). 1H NMR spectroscopic and histopathological studies on propyleneimine-induced renal papillary necrosis in the rat and the multimammate desert mouse (Mastomys natalensis). Comparative Biochemistry and Physiology, 116C, 125–134.
Holmes, E., Nicholson, J. K., Nicholls, A., et al. (1998). The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine. Chemometric Intelligent Lab Systems, 44, 245–255.
Huang, C. M., Chang, H. C., Kao, S. T., et al. (2011). Radial pressure pulse and heart rate variability in heat- and cold-stressed humans. Evidence-Based Complementary & Alternative Medicine, 1–9.
Janus, T., Borowiak, K. S., Mokrzyńska, A. M., Świniarski, A., & Rozwadowski, Z. (2005). 1H nuclear magnetic resonance spectroscopic investigation of urine for diagnostic and clinical assessment of methanol intoxication. Basic & Clinical Pharmacology & Toxicology, 97, 257–260.
Joca, S. R., Padovan, C. M., & Guimaraes, F. S. (2003). Stress, depression and the hippocampus. Revista Brasileira de Psiquiatria, 25, 46–51.
Kanayama, N., Khatun, S., Belayet, H., She, L., & Terao, T. (1999). Chronic local cold stress to the soles induces hypertension in rats. American Journal of Hypertension, 12, 1124–1129.
Kapil, A., & Sharma, S. (1997). Immunopotenting compounds from Tinospora Cordifolia. Journal of Ethnopharmacology, 58, 89–95.
Kulinskii, V. I., Medvedev, A. I., & Kuntsevich, A. K. (1986). Stimulation of mitochondrial oxidative enzymes in acute cooling and its catecholamine mechanisms. Voprosy Meditsinskoi Khimii, 32(5), 84–88.
Liu, Y., Huang, R., Liu, L., et al. (2010). Metabonomics study of urine from Sprague-Dawley rats exposed to Huang-yao-zi using 1H NMR spectroscopy. Journal of Pharmaceutical and Biomedical Analysis, 52, 136–141.
Lyte, M., & Bailey, M. T. (1997). Neuroendocrine-bacterial interactions in a neurotoxin-induced model of trauma. Journal of Surgical Research, 70, 195–201.
Mahdi, A. A., Annarao, S., Tripathi, S., et al. (2008). Correlation of age-related metabonomic changes in 1H NMR serum and urine profiles of rats with cognitive function. The Open Magnetic Resonance Journal, 1, 71–76.
Mathew, S., & Kuttan, G. (1998). Antioxidant activity of Tinospora cordifolia and its usefulness in the amelioration of cyclophosphamide induced toxicity. Journal of Experimental and Clinical Cancer Research, 16, 407–411.
Mathew, S., & Kuttan, G. (1999). Immunomodulatory and antitumor activities of Tinospora Cordifolia. Fitoterapia, 70, 35–43.
Michaud, M. R., Benoit, J. B., Lopez-Maratinez, G., et al. (2008). Metabolomics reveals unique and shared metabolic changes in response to heat shock, freezing and desiccation in the Antarctic midge. Belgica antarctica. J Insect Physiol, 54, 645–655.
Miller, D. B., & O’Callaghan, J. P. (2002). Neuroendocrine aspects of the response to stress. Metabolism, 51(6 Suppl. 1), 5–10.
Nagaraja, P. K., Kammar, K. F., & Devi, S. (2007). Modulation of morphology and some gluconeogenic enzymes activity by Tinospora cordifolia (Willd.) in diabetic rat kidney. Biomedical Research, 18(3), 179–183.
Nair, P. K., Rodriguez, S., & Ramachandran, R. (2004). Immune stimulating properties of a novel polysaccharide from the medicinal plant Tinospora cordifolia. International Immunopharmacology, 4, 1645–1659.
Nicholson, J. K., Ghauri, F. Y. K., & Blackledge, C. A. (1991). Use of high-field nuclear magnetic resonance spectroscopy for the analysis of biological fluids. Analytical Proceedings, 28, 217–223.
Nicholson, J. K., Lindon, J. C., & Holmes, E. (1999). ‘Metabonomics’: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 29, 1181–1189.
Nicholson, J. K., Sadler, P. J., Bales, J. R., Juul, S. M., Macleod, A. F., & Sonksen, P. H. (1984). Monitoring metabolic disease by proton NMR of urine. Lancet, 2, 751–752.
Nicholson, J. K., & Wilson, I. D. (2003). Understanding ‘Global’ systems biology: Metabonomics and the continuum of metabolism. Nature Reviews Drug Discovery, 2, 668–676.
Pacak, K., Palkovits, M., Kopin, I. J., & Goldstein, D. S. (1995). Stress induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary adrenocortical and sympathoadrenal activity: In vivo microdialysis studies. Frontiers in Neuroendocrinology, 16, 89–150.
Pahadiya, S., & Sharma, J. (2003). Alteration of lethal effects of gamma rays in Swiss albino mice by Tinospora cordifolia. Phytotherapy Research, 17, 552–554.
Panchabhai, T. S., Kulkarni, U. P., & Rege, N. N. (2008). Validation of therapeutic claims of Tinospora cordifolia: A review. Phytotherapy Research, 22, 425–441.
Purandare, H., & Supe, A. (2007). Immunomodulatory role of Tinospora cordifolia as an adjuvant in surgical treatment of diabetic foot ulcers: A prospective randomized controlled study. Indian Journal of Medical Sciences, 61, 347–355.
Rathi, S. S., Grover, J. K., Vikrant, V., & Biswas, N. R. (2002). Prevention of experimental diabetic cataract by Indian ayurvedic plant extract. Phytotherapy Research, 16, 774–777.
Rawal, A. K., Muddeshwar, M. G., & Biswas, S. K. (2004). Rubia Cordifolia, Fagonia Cretica linn and Tinospora Cordifolia exert neuroprotection by modulating the antioxidant system in rat hippocampal slices subjected to oxygen glucose deprivation. BMC Complementary and Alternative Medicine, 4, 11–20.
Rege, N. N., Thatte, U. M., & Dahanukar, S. A. (1999). Adaptogenic properties of six Rasayana herbs used in ayurvedic medicine. Phytotherapy Research, 13, 275–291.
Robosky, L. C., Robertson, D. G., Baker, J. D., Rane, S., & Reily, M. D. (2002). In vivo toxicity screening programs using metabonomics. Combinatorial Chemistry & High Throughput Screening, 5, 651–662.
Sharma, U., Chaudhury, K., Jagannathan, N. R., & Guha, S. K. (2001). A proton NMR study of the effect of a new intravasal injectable male contraceptive RISUG on seminal plasma metabolites. Reproduction, 122, 431–436.
Stanely, M. P., & Menon, V. P. (2001). Antioxidant action of Tinospora cordifolia root extract in alloxan diabetic rats. Phytotherapy Research, 15, 213–218.
Stanely, M. P., & Menon, V. P. (2003). Hypoglycaemic and hypolipidaemic action of alcohol extract of Tinospora cordifolia roots in chemical induced diabetes in rats. Phytotherapy Research, 17, 410–413.
Sterling, P., & Eyer, J. (1988). Allostasis: A new paradigm to explain arousal pathology. Handbook of life stress, cognition and health (pp. 629–649). New York: Wiley.
Subramanian, M., Chintalwar, G. J., & Chattopadhyay, S. (2002). Antioxidant properties of a Tinospora Cordifolia polysaccharide against iron-mediated lipid damage and gamma-ray induced protein damage. Redox Report, 7, 137–143.
Teague, C. R., Dhabhar, F. S., Barton, R. H., et al. (2007). Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague-Dawley rats. Journal of Proteome Research, 6, 2080–2093.
Thompson, D. G., Richelson, E., & Malagelada, J. R. (1983). Perturbation of upper gastrointestinal function by cold stress. Gut, 24(4), 277–283.
Vangala, S., & Tonelli, A. (2007). Biomarkers, metabonomics, and drug development: Can inborn errors of metabolism help in understanding drug toxicity? AAPS Journal, 9(3), E284–E297.
Wang, X., Zhao, T., Qiu, Y., et al. (2009). Metabonomics approach to understanding acute and chronic stress in rat models. Journal of Proteome Research, 8, 2511–2518.
Wazir, V., Maurya, R., & Kapil, R. S. (1995). Cordioside, a clerodane furano diterpene glucoside from T. cordifolia. Phytochemistry, 38, 447–449.
Williams, R. E., Jacobsen, M., & Lock, E. A. (2003). 1H NMR pattern recognition and 31P NMR studies with d-serine in rat urine and kidney, time- and dose-related metabolic effects. Chemical Research in Toxicology, 16, 1207–1216.
Zuppi, C., Messana, I., Forni, F., et al. (1997). 1H NMR spectra of normal urines: Reference ranges of the major metabolites. Clinica Chimica Acta, 265, 85–97.
Acknowledgments
This work was performed as a part of DRDO sponsored R & D project INM-308. The authors are thankful for the financial support provided by Defence Research & Development Organization (DRDO), Ministry of Defence, India.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gandhi, S., Devi, M.M., Pal, S. et al. Metabolic regulatory variations in rats due to acute cold stress & Tinospora Cordifolia intervention: high resolution 1H NMR approach. Metabolomics 8, 444–453 (2012). https://doi.org/10.1007/s11306-011-0326-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11306-011-0326-z