Exploring Neuroprotective Properties of Centella Asiatica Extract on Metabolic Change in Chronic Stress-Induced Rats
Stress is a mode of adaptive response towards external demands, and prolonged exposure to stress is known to promote aging and neurodegeneration. Several therapies promote neuroprotection but are usually accompanied by adverse consequences. Traditional medicine has been proven as an effective alternative for promoting pharmacological health benefits such as wound healing, boosting memory function and reducing oxidative stress. Centella asiatica (CeA) has also gaining attention as an alternative option in promoting neuroprotective activities against neurodegenerative disorders and neuronal injuries. In this study, the neurodegenerative condition of rats was achieved using chronic stress through movement restraint and forced swimming for 21 consecutive days. Here, the neuroprotective properties of three different dosage of CeA (200 mg/kg/day, 400 mg/kg/day and 800 mg/kg/day) was evaluated using metabolomics approach. The administration of CeA shown distinction between untreated group and treated group; and reducing the effect of chronic stress in rats. The extract also demonstrated a significant elevation in several metabolites (lactate, isoleucine, proline, methionine, valine, leucine and glutamine) in rats treated with CeA, particularly in rats administered with 800 mg/kg of CeA. These significant metabolites play important roles in variety of biochemical function of the brain such as the synthesis of protein, energy metabolism, synthesis of neurotransmitter, protection against oxidative stress and compartmentalisation of glutamate. The results of this study may contribute towards greater understanding of molecular mechanism of CeA in promoting neuroprotective properties against neurodegeneration from exposure to chronic stress.
Keywords: Centella asiatica, Chronic Stress, NMR-based metabolomics, Serum Metabolites
 Sannino, G., et al. (2016). Acute Stress Enhances the Expression of Neuroprotection- and NeurogenesisAssociated Genes in the Hippocampus of a Mouse Restraint Model. Oncotarget, vol. 7, issue 8, pp. 8455-8465.
 Bhagya, V., Christofer, T. and Shankaranarayana, R. B. (2016). Neuroprotective Effect of Celastrus Paniculatus on Chronic Stress-Induced Cognitive Impairment. Indian J Pharmacol, vol. 48, issue 6, pp. 687-693.
 McEwen, B. (2012). The Ever-Changing Brain: Cellular and Molecular Mechanisms for the Effects of Stressful Experiences. Dev Neurobiol, vol. 72, issue 6, pp. 872-890.
 Pinto, V., et al. (2015). Differential Impact of Chronic Stress along the Hippocampal Dorsal-Ventral Axis. Brain Struc Funct, vol. 220, issue 2, pp. 1205-1212.
 Mishra, S. (2015). Ethnopharmacological Importance of Centella Asiatica with Special Reference to Neuroprotective Activity. Asian J Pharmacol Toxicol, vol. 3, issue 10, pp. 49-53.
 Somboonwong, J., et al. (2012). Wound Healing Activities of Different Extracts of Centella Asiatica in Incision and Burn Wound Models: An Experimental Animal Study. BMC Complem Altern Med, issue 103,
 Sainath, S., et al. (2011). Protective Role of Centella Asiatica on Lead- Induced Oxidative Stress and Suppressed Reproductive Health in Male Rats. Environ Toxicol Pharmacol, vol. 32, issue 2, pp. 146-154.
 Nasir, M., et al. (2011). Effects of Asiatic Acid on Passive and Active Avoidance Task in Male SpraqueDawley Rats. J Ethnopharmacol, vol. 134, issue 2, pp. 203-209.
 Haleagrahara, N. and Ponnusamy. K. (2010). Neuroprotective Effect of Centella Asiatica Extract (CAE) on Experimentally Induced Parkinsonism in Aged Sprague-Dawley Rats. J Toxicol Sci, vol. 35, issue 1, pp. 41-47.
 Gray, N., et al. (2015). Centella asiatica Attenuates Amyloid-β-Induced Oxidative Stress and Mitochondrial Dysfunction. J Alzheimers Dis, vol. 45, issue 3, pp. 933-946.
 Nicholson, J. and Wilson, I. (1989). High Resolution Proton Magnetic Resonance Spectroscopy of Biological Fluids. Prog Nucl Magn Reson Spectrosc, vol. 21, issue 4-5, pp. 449-501.
 Mickiewicz, B., et al. (2014). Metabolic Profiling of Serum Samples by 1H NMR Spectroscopy as a Potential Diagnostic Approach for Septic Shock. Crit Care Med, vol. 42, issue 5, pp. 1140-1149.
 Jung, Y. S., et al. (2016). Software-Assisted Serum Metabolite Quantification using NMR. Anal Chim Acta, issue 934, pp. 194-202.
 Gallagher, C. N., et al. (2009). The Human Brain Utilizes Lactate Via the Tricarboxylic Acid Cycle: A 13C-Labelled Microdialysis and High- Resolution Nuclear Magnetic Resonance Study. Brain, vol. 132, issue 10, pp. 2839-2849.
 Pellerin, L., et al. (2007). Activity-Dependent Regulation of Energy Metabolism by Astrocytes: An Update. Glia, vol. 55, issue 12, pp. 1251-1262.
 Hu, Y. and Wilson, G. (1997). A Temporary Local Energy Pool Coupled to Neuronal Activity: Fluctuations of Extracellular Lactate Levels in Rat Brain Monitored with Rapid-Response Enzyme-Based Sensor. J Neurochem, vol. 69, issue 4, pp. 1484-1490.
 Fernstorm, J. (2005). Branched-Chain Amino Acids and Brain Function. J Nutr., vol. 135, issue 6, pp. 1539-1546.
 Zhao, J., et al. (2015). Metabolomic Identification of Biochemical Changes Induced by Fluoxetine and Imipramine in a Chronic Mild Stress Mouse Model of Depression. Scie Rep, issue 5. 10.1038/srep08890
 Choi, S., et al. (2013). Oral Branched-Chain Amino Acid Supplements that Reduce Brain Serotonin during Exercise in Rats Also Lower Brain Catecholamines. Amino Acids, vol. 45, issue 5, pp. 1133-1142.
 Raol, Y., Lynch, D. and Brooks-Kayal, A. (2001). Role of Excitatory Amino Acids in Developmental Epilepsies. Mental Retardation and Developmental Disabilities Research Reviews, vol. 7, issue 4, pp. 254-60.
 Massucci, F., et al. (2013). Energy Metabolism and Glutamate-Glutamine Cycle in the Brain: A Stoichiometric Modeling Perspective. BMC Syst Biol, vol. 7, issue 103. DOI: 10.1186/1752-0509-7-103
 Newsholme, P., et al. (2003). Glutamine and Glutamate—Their Central Role in Cell Metabolism and Function. Cell Biochem Funct, vol. 21, issue 1, pp. 1-9.
 Budnik, V. and Salinas, P. (2011). Wnt Signaling during Synaptic Development and Plasticity. Current Opinion in Neurobiology, vol. 21, issue 1, pp. 151-159.
 Kaul, S., Sharma, S. and Mehta, I. (2008). Free Radical Scavenging Potential of L-Proline: Evidence from in Vitro Assays. Amino Acids, vol. 34, issue 2, pp. 315-320.
 Li, H., et al. (2016). The Metabolities of Glutamine Prevent Hydroxyl Radical-Induced Apoptosis through Inhibiting Mitochondria and Calcium Íon Involved in Fish Erytrocytes. Free Radical Biology and Medicineissue 92, pp. 96-140.
 Finkelstein, J. (1990). Methionine Metabolism in Mammals. J Nutr Biochem, vol. 1, issue 5, pp. 228-237.
 Bolander-Gouaille, C. and Bottiglieri, T. (2007). Homocysteine: Related Vitamins and Neuropsychiatric Disorders (2nd ed.). Paris: Springer-Verlag.