Abstract
Intermittent fasting-dietary restriction (IF-DR) is an increasingly popular intervention to promote healthy aging and delay age associated decline in brain functions. Also, the use of herbal interventions is gaining attention due to their non-pharmacological approach to treat several abnormalities and promote general health with least side effects. The present study was aimed to investigate the synergistic effects of IF-DR regimen with herbal supplementation on anxiety-like behavior and neuroinflammation in middle aged female rats. We used dried leaf powder of Withania somnifera and dried stem powder of Tinospora cordifolia for our study. The rats were divided into three groups: (1) Control group fed ad libitum (AL); (2) rats deprived of food for full day and fed ad libitum on every alternate day (IF-DR); and (3) IF-DR and herbal extract (DRH) group in which rats were fed ad libitum with herbal extract supplemented diet, every alternate day. Post regimen, the rats were tested for anxiety-like behavior and further used for study of key inflammatory molecules (NFκB, Iba1, TNFα, IL-1β, IL-6) and glial marker (GFAP) in hippocampus and piriform cortex regions of brain. The study was further extended to explore the effect of DRH regimen on stress response protein (HSP70) and calcium dependent regulators of synaptic plasticity (CaMKIIα, Calcineurin). Our data demonstrated that DRH regimen reduced anxiety-like behavior in middle age female rats and associated neuroinflammation by ameliorating key inflammatory cytokines and modulated stress response. The present data may provide scientific validation for anxiolytic and anti-inflammatory potential of herbal intervention combined with short term IF-DR regimen.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Achour SB, Pascual O (2010) Glia: the many ways to modulate synaptic plasticity. Neurochem Int 57(4):440–445. doi:10.1016/j.neuint.2010.02.013
Andallu B, Radhika B (2000) Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera, Dunal) root. Indian J Exp Biol 38(6):607–609
Arumugam TV, Phillips TM, Cheng A, Morrell CH, Mattson MP, Wan R (2010) Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann Neurol 67(1):41–52. doi:10.1002/ana.21798
Bhattacharya SK, Bhattacharya A, Sairam K, Ghosal S (2000) Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study. Phytomedicine 7(6):463–469. doi:10.1016/S0944-7113(00)80030-6
Bishayi B, Roychowdhury S, Ghosh S, Sengupta M (2002) Hepatoprotective and immunomodulatory properties of Tinospora cordifolia in CCl4 intoxicated mature albino rats. J Toxicol Sci 27(3):139–146
Castello L, Froio T, Maina M, Cavallini G, Biasi F, Leonarduzzi G, Donati A, Bergamini E, Poli G, Chiarpotto E (2010) Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation. Free Radic Biol Med 48(1):47–54. doi:10.1016/j.freeradbiomed.2009.10.003
Conde JR, Streit WJ (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65(3):199–203. doi:10.1097/01.jnen.0000202887.22082.63
De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 15(26):3003–3026
Deocaris CC, Widodo N, Wadhwa R, Kaul SC (2008) Merger of ayurveda and tissue culture-based functional genomics: inspirations from systems biology. J Transl Med 6(1):14. doi:10.1186/1479-5876-6-14
Douglass JD, Dorfman MD, Thaler JP (2017) Glia: silent partners in energy homeostasis and obesity pathogenesis. Diabetologia 60(2):226–236. doi:10.1007/s00125-016-4181-3
Duan W, Guo Z, Jiang H, Ware M, Mattson MP (2003) Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology 144(6):2446–2453. doi:10.1210/en.2002-0113
Grosjean J, Kiriakidis S, Reilly K, Feldmann M, Paleolog E (2006) Vascular endothelial growth factor signalling in endothelial cell survival: a role for NFκB. Biochem Biophys Res Commun 340(3):984–994. doi:10.1016/j.bbrc.2005.12.095
Gupta M, Kaur G (2016) Aqueous extract from the Withania somnifera leaves as a potential anti-neuroinflammatory agent: a mechanistic study. J Neuroinflamm 13(1):193. doi:10.1186/s12974-016-0650-3
Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, Martin B, Cutler RG, Evans G, Whiteside S, Maudsley S, Camandola S, Wang R, Carlson OD, Egan JM, Mattson MP, Howell A (2013) The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr 110(8):1534–1547. doi:10.1017/S0007114513000792
Horne BD, Muhlestein JB, Anderson JL (2015) Health effects of intermittent fasting: hormesis or harm? A systematic review. Am J Clin Nutr 102(2):464–470. doi:10.3945/ajcn.115.109553
Jeong MA, Plunet W, Streijger F, Lee JH, Plemel JR, Park S, Lam CK, Liu J, Tetzlaff W (2011) Intermittent fasting improves functional recovery after rat thoracic contusion spinal cord injury. J Neurotrauma 28(3):479–492. doi:10.1089/neu.2010.1609
Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD, Pearson M, Nassar M, Telljohann R, Maudsley S, Carlson O, John S, Laub DR, Mattson MP (2007) Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med 42(5):665–674. doi:10.1016/j.freeradbiomed.2006.12.005
Kakimura J, Kitamura Y, Takata K, Tsuchiya D, Taniguchi T, Gebicke-Haerter PJ, Smith MA, Perry G, Shimohama S (2002) Possible Involvement of ER Chaperone Grp78 on reduced formation of amyloid-β deposits. Ann N Y Acad Sci 977(1):327–332
Kalueff AV, Tuohimaa P (2005) The grooming analysis algorithm discriminates between different levels of anxiety in rats: potential utility for neurobehavioural stress research. J Neurosci Methods 143(2):169–177. doi:10.1016/j.jneumeth.2004.10.001
Karin M, Delhase M (2000) The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling. Semin Immunol 12(1):85–98. doi:10.1006/smim.2000.0210
Kataria H, Kumar S, Chaudhary H, Kaur G (2016) Withania somnifera suppresses tumor growth of intracranial allograft of glioma cells. Mol Neurobiol 53(6):4143–4158. doi:10.1007/s12035-015-9320-1
Kaur T, Singh H, Mishra R, Manchanda S, Gupta M, Saini V, Sharma A, Kaur G (2017) Withania somnifera as a potential anxiolytic and immunomodulatory agent in acute sleep deprived female Wistar rats. Mol Cell Biochem 427(1):91–101. doi:10.1007/s11010-016-2900-1
Klee CB, Ren H, Wang X (1998) Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. J Biol Chem 273(22):13367–13370
Lara-Padilla E, Godínez-Victoria M, Drago-Serrano ME, Reyna-Garfias H, Arciniega-Martínez IM, Abarca-Rojano E, Cruz-Hernandez TR, Campos-Rodríguez R (2015) Intermittent fasting modulates IgA levels in the small intestine under intense stress: a mouse model. J Neuroimmunol 285:22–30. doi:10.1016/j.jneuroim.2015.05.013
Lisman J, Raghavachari S (2015) Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex. Brain Res 1621:51–61. doi:10.1016/j.brainres.2014.12.010
Manchanda S, Mishra R, Singh R, Kaur T, Kaur G (2017) Aqueous leaf extract of Withania somnifera as a potential neuroprotective agent in sleep-deprived rats: a mechanistic study. Mol Neurobiol 54(4):3050–3061. doi:10.1007/s12035-016-9883-5
Mattson MP, Longo VD, Harvie M (2016) Impact of intermittent fasting on health and disease processes. Ageing Res Rev. doi:10.1016/j.arr.2016.10.005
Mishra R, Kaur G (2013) Aqueous ethanolic extract of Tinospora cordifolia as a potential candidate for differentiation based therapy of glioblastomas. PLoS ONE 8(10):e78764. doi:10.1371/journal.pone.0078764
Mishra R, Kaur G (2015) Tinospora cordifolia induces differentiation and senescence pathways in neuroblastoma cells. Mol Neurobiol 52(1):719–733. doi:10.1007/s12035-014-8892-5
Mishra R, Manchanda S, Gupta M, Kaur T, Saini V, Sharma A, Kaur G (2016) Tinospora cordifolia ameliorates anxiety-like behavior and improves cognitive functions in acute sleep deprived rats. Sci Rep 6:25564. doi:10.1038/srep25564
Nin MS, Couto-Pereira NS, Souza MF, Azeredo LA, Ferri MK, Dalprá WL, Gomez R, Barros HM (2012) Anxiolytic effect of clonazepam in female rats: grooming microstructure and elevated plus maze tests. Eur J Pharmacol 684(1–3):95–101. doi:10.1016/j.ejphar.2012.03.038
Patil S (2016) Evaluation of anxiolytic and antidepressant effect of different dosage forms of the Guduchi. Int J Green Pharm 9(4):S25
Rasool M, Varalakshmi P (2006) Immunomodulatory role of Withania somnifera root powder on experimental induced inflammation: an in vivo and in vitro study. Vascul Pharmacol 44(6):406–410. doi:10.1016/j.vph.2006.01.015
Rodriguez-Melendez R, Schwab LD, Zempleni J (2004) Jurkat cells respond to biotin deficiency with increased nuclear translocation of NF-kB, mediating cell survival. Int J Vitam Nutr Res 74(3):209–216. doi:10.1024/0300-9831.74.3.209
Saavedra JM, Sánchez-Lemus E, Benicky J (2011) Blockade of brain angiotensin II AT 1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology 36(1):1–18. doi:10.1016/j.psyneuen.2010.10.001
Salim S, Chugh G, Asghar M (2012) Inflammation in anxiety. Adv Protein Chem Struct Biol 88:1–25. doi:10.1016/B978-0-12-398314-5.00001-5
Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T (2008) Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 7(2):83–105. doi:10.1016/j.arr.2007.09.002
Sangeetha MK, Raghavendran HRB, Gayathri V, Vasanthi HR (2011) Tinospora cordifolia attenuates oxidative stress and distorted carbohydrate metabolism in experimentally induced type 2 diabetes in rats. J Nat Med 65(3–4):544–550. doi:10.1007/s11418-011-0538-6
Sarkar D, Fisher PB (2006) Molecular mechanisms of aging-associated inflammation. Cancer Lett 236(1):13–23. doi:10.1016/j.canlet.2005.04.009
Saur L, de Senna PN, Paim MF, Do Nascimento P, Ilha J, Bagatini PB, Achaval M, Xavier LL (2014) Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes. Brain Struct Funct 219(1):293–302. doi:10.1007/s00429-012-0500-8
Sharma S, Kaur G (2005) Neuroprotective potential of dietary restriction against kainate-induced excitotoxicity in adult male Wistar rats. Brain Res Bull 67(6):482–491. doi:10.1016/j.brainresbull.2005.07.015
Singh R, Lakhanpal D, Kumar S, Sharma S, Kataria H, Kaur M, Kaur G (2012) Late-onset intermittent fasting dietary restriction as a potential intervention to retard age-associated brain function impairments in male rats. Age 34(4):917–933. doi:10.1007/s11357-011-9289-2
Singh R, Manchanda S, Kaur T, Kumar S, Lakhanpal D, Lakhman SS, Kaur G (2015) Middle age onset short-term intermittent fasting dietary restriction prevents brain function impairments in male Wistar rats. Biogerontology 16(6):775–788. doi:10.1007/s10522-015-9603-y
Sparkman NL, Johnson RW (2008) Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. NeuroImmunoModulation 15(4–6):323–330. doi:10.1159/000156474
Subramanian M, Chintalwar GJ, Chattopadhyay S (2002) Antioxidant properties of a Tinospora cordifolia polysaccharide against iron-mediated lipid damage and γ-ray induced protein damage. Redox Rep 7(3):137–143. doi:10.1179/135100002125000370
Tinsley GM, La Bounty PM (2015) Effects of intermittent fasting on body composition and clinical health markers in humans. Nutr Rev 73(10):661–674. doi:10.1093/nutrit/nuv041
Udayakumar R, Kasthurirengan S, Mariashibu TS, Rajesh M, Anbazhagan VR, Kim SC, Ganapathi A, Choi CW (2009) Hypoglycaemic and hypolipidaemic effects of Withania somnifera root and leaf extracts on alloxan-induced diabetic rats. Int J Mol Sci 10(5):2367–2382. doi:10.3390/ijms10052367
Van Cauwenberghe C, Vandendriessche C, Libert C, Vandenbroucke RE (2016) Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease. Mamm Genome 27(7–8):300–319. doi:10.1007/s00335-016-9647-6
Vasconcelos AR, Yshii LM, Viel TA, Buck HS, Mattson MP, Scavone C, Kawamoto EM (2014) Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment. J Neuroinflammation 11(1):85. doi:10.1186/1742-2094-11-85
Vasconcelos AR, Kinoshita PF, Yshii LM, Orellana AMM, Böhmer AE, de Sá Lima L, Alves R, Andreotti DZ, Marcourakis T, Scavone C, Kawamoto EM (2015) Effects of intermittent fasting on age-related changes on Na, K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus. Neurobiol Aging 36(5):1914–1923. doi:10.1016/j.neurobiolaging.2015.02.020
Vink D, Aartsen MJ, Comijs HC, Heymans MW, Penninx BW, Stek ML, Deeg DJ, Beekman AT (2009) Onset of anxiety and depression in the aging population: comparison of risk factors in a 9-year prospective study. Am J Geriatr Psychiatry 17(8):642–652
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328. doi:10.1038/nprot.2007.44
Wan R, Camandola S, Mattson MP (2003) Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats. J Nutr 133(6):1921–1929
Zaman A, Khan MSS, Akter L, Syeed SH, Akter J, Al Mamun A, Alam ME, Habib MA, Jalil MA (2015) Exploring new pharmacology and toxicological screening and safety evaluation of one widely used formulation of Nidrakar Bati from South Asia region. BMC Complement Altern Med 15(1):121. doi:10.1186/s12906-015-0635-2
Acknowledgements
Harpal Singh is thankful to DST, GOI for fellowship grant during the entire course of study. Taranjeet Kaur and Shaffi Manchanda are thankful to University Grants Commission (UGC), GOI for fellowship grant during the entire course of study. Infrastructure provided by UGC under University with Potential for Excellence (UPE) and Centre with Potential for Excellence in Particular Area (CPEPA) schemes and DBT under DISC facility is highly acknowledged. The funding source had no role in study design; collection, analysis and interpretation of data; in writing of report; and in decision to submit the article for publication.
Funding
The current research work was funded by Department of Biotechnology (DBT), Government of India (GOI) and Department of Science and Technology (DST), GOI grants to Gurcharan Kaur.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
Rights and permissions
About this article
Cite this article
Singh, H., Kaur, T., Manchanda, S. et al. Intermittent fasting combined with supplementation with Ayurvedic herbs reduces anxiety in middle aged female rats by anti-inflammatory pathways. Biogerontology 18, 601–614 (2017). https://doi.org/10.1007/s10522-017-9706-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-017-9706-8