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Withania somnifera as a potential anxiolytic and immunomodulatory agent in acute sleep deprived female Wistar rats

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Abstract

Sleep is a profound regulator of cellular immunity, and the curtailment of sleep in present day lifestyle leads to disruption of neuro-immune–endocrine interactions. No therapeutic remedy is yet known for the amelioration of detrimental effects caused by sleep deprivation (SD). The current study was aimed to elucidate the effects of acute SD on immune function and its modulation by water extract from leaves of Withania somnifera (ASH-WEX). Three groups of animals, i.e. Vehicle-Undisturbed sleep (VUD), Vehicle-Sleep deprived (VSD) and ASH-WEX fed sleep deprived (WSD) rats were tested for their anxiety-like behaviour and further used for the study of inflammatory and apoptotic markers expression in piriform cortex and hippocampus regions of the brain. VSD animals showed high level of anxiety in elevated plus maze test, which was ameliorated in WSD group. The stress induced expression of inflammatory and immune response markers GFAP, TNFα, IL-6, OX-18 and OX-42 in VSD animals was found to be modulated by ASH-WEX. Further, the stress induced apoptosis was suppressed in WSD group as indicated by expression of NF-κB, AP-1, Bcl-xL and Cytochrome c. This study provides scientific validation to the anxiolytic, anti-inflammatory and anti-apoptotic properties of ASH-WEX, which may serve as an effective dietary supplement for management of SD induced stress and associated functional impairments.

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References

  1. Rasch B, Born J (2013) About sleep’s role in memory. Physiol Rev 93:681–766. doi:10.1152/physrev.00032.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Knutson KL, Ryden AM, Mander BA, Van Cauter E (2006) Role of sleep duration and quality in the risk and severity of type 2 diabetes mellitus. Arch Intern Med 166:1768–1774. doi:10.1001/archinte.166.16.1768

    Article  PubMed  Google Scholar 

  3. Von Ruesten A, Weikert C, Fietze I, Boeing H (2012) Association of sleep duration with chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. PLOS ONE 7:e30972. doi:10.1371/journal.pone.0030972

    Article  Google Scholar 

  4. Ohkuma T, Fujii H, Iwase M, Kikuchi Y, Ogata S, Idewaki Y, Ide H, Doi Y, Hirakawa Y, Nakamura U, Kitazono T (2013) Impact of sleep duration on obesity and the glycemic level in patients with type 2 diabetes the Fukuoka diabetes registry. Diabetes Care 36:611–617

    Article  PubMed  PubMed Central  Google Scholar 

  5. Palagini L, Maria Bruno R, Gemignani A, Baglioni C, Ghiadoni L, Riemann D (2013) Sleep loss and hypertension: a systematic review. Curr Pharm Design 19:2409–2419

    Article  CAS  Google Scholar 

  6. Ferrie JE, Kivimäki M, Akbaraly TN, Singh-Manoux A, Miller MA, Gimeno D, Kumari M, Smith GD, Shipley MJ (2013) Associations between change in sleep duration and inflammation: findings on C-reactive protein and interleukin 6 in the Whitehall II Study. Am J Epidemiol. doi:10.1093/aje/kwt072

    PubMed  PubMed Central  Google Scholar 

  7. Hovhannisyan LP, Mkrtchyan GM, Boyajyan AS, Avetyan DG, Tadevosyan MY, Sukiasyan SH (2012) Inflammatory markers in post-traumatic stress disorder. Cytokines Inflamm 11:42–45

    Google Scholar 

  8. Chen W, Lin H, Zhong X, Liu Z, Geng Y, Xie C, Chen W (2014) Discrepant expression of cytokines in inflammation-and age-related cataract patients. PLOS ONE 9:e109647. doi:10.1371/journal.pone.0109647

    Article  PubMed  PubMed Central  Google Scholar 

  9. Besedovsky L, Lange T, Born J (2012) Sleep and immune function. Pflug Arch Eur J Physiol 463:121–137. doi:10.1007/s00424-011-1044-0

    Article  CAS  Google Scholar 

  10. Gómez-González B, Domínguez-Salazar E, Hurtado-Alvarado G, Esqueda-Leon E, Santana-Miranda R, Rojas-Zamorano JA, Velázquez-Moctezuma J (2012) Role of sleep in the regulation of the immune system and the pituitary hormones. Ann NY Acad Sci 1261:97–106. doi:10.1111/j.1749-6632.2012.06616.x

    Article  PubMed  Google Scholar 

  11. Irwin MR (2015) Why sleep is important for health: a psychoneuroimmunology perspective. Psychology 66:143–172. doi:10.1146/annurev-psych-010213-115205

    Article  Google Scholar 

  12. Vgontzas AN, Fernandez-Mendoza J, Liao D, Bixler EO (2013) Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep Med Rev 17:241–254. doi:10.1016/j.smrv.2012.09.005

    Article  PubMed  PubMed Central  Google Scholar 

  13. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S (2006) Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 166:1756–1762. doi:10.1001/archinte.166.16.1756

    Article  CAS  PubMed  Google Scholar 

  14. Ogawa Y, Kanbayashi T, Saito Y, Takahashi Y, Kitajima T, Takahashi K, Hishikawa Y, Shimizu T (2003) Total sleep deprivation elevates blood pressure through arterial baroreflex resetting: a study with microneurographic technique. Sleep 26:986–989

    PubMed  Google Scholar 

  15. Joo EY, Yoon CW, Koo DL, Kim D, Hong SB (2012) Adverse effects of 24 hours of sleep deprivation on cognition and stress hormones. J Clin Neurol 8:146–150. doi:10.3988/jcn.2012.8.2.146

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tilley AJ, Empson JAC (1978) REM sleep and memory consolidation. Biol Psychol 6:293–300. doi:10.1016/0301-0511(78)90031-5

    Article  CAS  PubMed  Google Scholar 

  17. Walker MP, Stickgold R (2006) Sleep, memory and plasticity. Annu Rev Psychol 57:139–166. doi:10.1146/annurev.psych.56.091103.070307

    Article  PubMed  Google Scholar 

  18. Shah N, Singh R, Sarangi U, Saxena N, Chaudhary A, Kaur G, Kaul SC, Wadhwa R (2015) Combinations of Ashwagandha leaf extracts protect brain-derived cells against oxidative stress and induce differentiation. PLOS ONE 10:e0120554. doi:10.1371/journal.pone.0120554

    Article  PubMed  PubMed Central  Google Scholar 

  19. Al-Hindawi MK, Al-Khafaji SH, Abdul-Nabi MH (1992) Anti-granuloma activity of Iraqi Withania somnifera. J Ethnopharmacol 37:113–116. doi:10.1016/0378-8741(92)90069-4

    Article  CAS  PubMed  Google Scholar 

  20. Singh RH, Narsimhamurthy K, Singh G (2008) Neuronutrient impact of Ayurvedic Rasayana therapy in brain aging. Biogerontology 9:369–374. doi:10.1007/s10522-008-9185-z

    Article  PubMed  Google Scholar 

  21. Bhattacharya A, Ghosal S, Bhattacharya S (2001) Anti-oxidant effect of Withania somnifera glycowithanolides in chronic foot shock stress-induced perturbations of oxidative free radical scavenging enzymes and lipid peroxidation in rat frontal cortex and striatum. J Ethnopharmacol 74:1–6. doi:10.1016/S0378-8741(00)00309-3

    Article  CAS  PubMed  Google Scholar 

  22. Govindarajan R, Vijayakumar M, Pushpangadan P (2005) Antioxidant approach to disease management and the role of ‘Rasayana’ herbs of Ayurveda. J Ethnopharmacol 99:165–178. doi:10.1016/j.jep.2005.02.035

    Article  CAS  PubMed  Google Scholar 

  23. 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 44:406–410. doi:10.1016/j.vph.2006.01.015

    Article  CAS  PubMed  Google Scholar 

  24. Verma SK, Kumar A (2011) Therapeutic uses of Withania somnifera (Ashwagandha) with a note on withanolides and its pharmacological actions. Asian J Pharm Clin Res 4:1–4

    CAS  Google Scholar 

  25. Baitharu I, Jain V, Deep SN, Hota KB, Hota SK, Prasad D, Ilavazhagan G (2013) Withania somnifera root extract ameliorates hypobaric hypoxia induced memory impairment in rats. J Ethnopharmacol 145:431–441. doi:10.1016/j.jep.2012.10.063

    Article  PubMed  Google Scholar 

  26. Chandrasekhar K, Kapoor J, Anishetty S (2012) A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med 34:255–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khyati SS, Anup TB (2013) A randomized double blind placebo controlled study of ashwagandha on generalized anxiety disorder. Int Ayurvedic Med J 1:1–7

    Google Scholar 

  28. Pratte MA, Nanavati KB, Young V, Morley CP (2014) An alternative treatment for anxiety: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withania somnifera). J Altern Complement Med 20:901–908. doi:10.1089/acm.2014.0177

    Article  PubMed  PubMed Central  Google Scholar 

  29. Pingali U, Pilli R, Fatima N (2014) Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy Res 6:12–18. doi:10.4103/0974-8490.122912

    Article  PubMed  PubMed Central  Google Scholar 

  30. Harikrishnan R, Balasundaram C, Jawahar S, Heo MS (2012) Immunomodulatory effect of Withania somnifera supplementation diet in the giant freshwater prawn Macrobrachium rosenbergii (de Man) against Aeromonas hydrophila. Fish Shellfish Immun 32:94–100. doi:10.1016/j.fsi.2011.10.027

    Article  CAS  Google Scholar 

  31. Sachdeva H, Sehgal R, Kaur S (2013) Studies on the protective and immunomodulatory efficacy of Withania somnifera along with cisplatin against experimental visceral leishmaniasis. Parasitol Res 112:2269–2280. doi:10.1007/s00436-013-3387-2

    Article  PubMed  Google Scholar 

  32. Kataria H, Shah N, Kaul SC, Wadhwa R, Kaur G (2011) Water extract of ashwagandha leaves limits proliferation and migration, and induces differentiation in glioma cells. Evid Based Complement Alternat Med. doi:10.1093/ecam/nep188

    PubMed  PubMed Central  Google Scholar 

  33. Kataria H, Gupta M, Lakhman SS, Kaur G (2015) Withania somnifera aqueous extract facilitates the expression and release of GnRH: in vitro and in vivo study. Neurochem Int 89:111–119. doi:10.1016/j.neuint.2015.08.001

    Article  CAS  PubMed  Google Scholar 

  34. Silva RH, Kameda SR, Carvalho RC, Takatsu-Coleman AL, Niigaki ST, Abilio VC, Tufik S, Frussa-Filho R (2004) Anxiogenic effect of sleep deprivation in the elevated plus-maze test in mice. Psychopharmacology 176:115–122. doi:10.1007/s00213-004-1873-z

    Article  CAS  PubMed  Google Scholar 

  35. Knutson KL, Spiegel K, Penev P, Van Cauter E (2007) The metabolic consequences of sleep deprivation. Sleep Med Rev 11:163–178. doi:10.1016/j.smrv.2007.01.002

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chiang CS, Stalder A, Samimi A, Campbell IL (1994) Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice. Dev Neurosci 16:212–221. doi:10.1159/000112109

    Article  CAS  PubMed  Google Scholar 

  37. Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW (2004) Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 89:1092–1100. doi:10.1111/j.1471-4159.2004.02420.x

    Article  CAS  PubMed  Google Scholar 

  38. Sofroniew MV (2013) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. The Neuroscientist. doi:10.1177/1073858413504466

    PubMed  Google Scholar 

  39. Salim S, Chugh G, Asghar M (2012) Inflammation in anxiety. Adv Protein Chem Struct Biol 88:1–25

    Article  CAS  PubMed  Google Scholar 

  40. Wakita T, Shintani F, Yagi G, Asai M, Nozawa S (2001) Combination of inflammatory cytokines increases nitrite and nitrate levels in the paraventricular nucleus of conscious rats. Brain Res 905:12–20. doi:10.1016/S0006-8993(01)02346-0

    Article  CAS  PubMed  Google Scholar 

  41. Kvietys PR, Granger DN (2012) Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Radical Bio Med 52:556–592. doi:10.1016/j.freeradbiomed.2011.11.002

    Article  CAS  Google Scholar 

  42. Wang J, Song N, Jiang H, Wang J, Xie J (2013) Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. BBA-Mol Basis Dis 1832:618–625. doi:10.1016/j.bbadis.2013.01.021

    Article  CAS  Google Scholar 

  43. Salim S, Sarraj N, Taneja M, Saha K, Tejada-Simon MV, Chugh G (2010) Moderate treadmill exercise prevents oxidative stress-induced anxiety-like behavior in rats. Behav Brain Res 208:545–552. doi:10.1016/j.bbr.2009.12.039

    Article  CAS  PubMed  Google Scholar 

  44. Patki G, Solanki N, Atrooz F, Allam F, Salim S (2013) Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 1539:73–86. doi:10.1016/j.brainres.2013.09.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yehuda S, Sredni B, Carasso RL, Kenigsbuch-Sredni D (2009) REM sleep deprivation in rats results in inflammation and interleukin-17 elevation. J Interf Cytok Res 29:393–398. doi:10.1089/jir.2008.0080

    Article  CAS  Google Scholar 

  46. Irwin MR, Wang M, Ribeiro D, Cho HJ, Olmstead R, Breen EC, Martinez-Maza O, Cole S (2008) Sleep loss activates cellular inflammatory signaling. Biol Psychiat 64:538–540. doi:10.1016/j.biopsych.2008.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mullington JM, Haack M, Toth M, Serrador JM, Meier-Ewert HK (2009) Cardiovascular, inflammatory, and metabolic consequences of sleep deprivation. Prog Cardiovasc Dis 51:294–302. doi:10.1016/j.pcad.2008.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M (2010) Sleep loss and inflammation. Best Pract Res Cl En 24:775–784. doi:10.1016/j.beem.2010.08.014

    Article  CAS  Google Scholar 

  49. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553. doi:10.1152/physrev.00011.2010

    Article  CAS  PubMed  Google Scholar 

  50. Simard AR, Rivest S (2004) Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 18:998–1000

    CAS  PubMed  Google Scholar 

  51. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313. doi:10.1002/jnr.20562

    Article  CAS  PubMed  Google Scholar 

  52. Suzumura A (2013) Neuron-microglia interaction in neuroinflammation. Curr Protein Pept Sci 14:16–20

    Article  CAS  PubMed  Google Scholar 

  53. Makarov SS (2001) NF-kappaB in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res 3:200–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Killeen MJ, Linder M, Pontoniere P, Crea R (2014) NF-κβ signaling and chronic inflammatory diseases: exploring the potential of natural products to drive new therapeutic opportunities. Drug Discov Today 19:373–378. doi:10.1016/j.drudis.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  55. Singh D, Aggarwal A, Maurya R, Naik S (2007) Withania somnifera inhibits NF-κB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells. Phytother Res 21:905–913. doi:10.1002/ptr.2180

    Article  CAS  PubMed  Google Scholar 

  56. Sivamani S, Joseph B, Kar B (2014) Anti-inflammatory activity of Withania somnifera leaf extract in stainless steel implant induced inflammation in adult zebrafish. J Genet Eng Biotechnol 12:1–6. doi:10.1016/j.jgeb.2014.01.002

    Article  Google Scholar 

  57. Uddin Q, Samiulla L, Singh VK, Jamil SS (2012) Phytochemical and pharmacological profile of Withania somnifera dunal: a review. J Appl Pharm Sci 02:170–175

    Google Scholar 

  58. Jacobs-Helber SM, Wickrema A, Birrer MJ, Sawyer ST (1998) AP1 regulation of proliferation and initiation of apoptosis in erythropoietin-dependent erythroid cells. Mol Cell Biol 18:3699–3707. doi:10.1128/MCB.18.7.3699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sandur SK, Ichikawa H, Pandey MK, Kunnumakkara AB, Sung B, Sethi G, Aggarwal BB (2007) Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radical Bio Med 43:568–580. doi:10.1016/j.freeradbiomed.2007.05.009

    Article  CAS  Google Scholar 

  60. Biswas S, Mishra P, Mallick BN (2006) Increased apoptosis in rat brain after rapid eye movement sleep loss. Neuroscience 142:315–331. doi:10.1016/j.neuroscience.2006.06.026

    Article  CAS  PubMed  Google Scholar 

  61. Zhang B, Hata R, Zhu P, Sato K, Wen TC, Yang L, Fujita H, Mitsuda N, Tanaka J, Samukawa K, Maeda N (2006) Prevention of ischemic neuronal death by intravenous infusion of a ginseng saponin, ginsenoside Rb1, that upregulates Bcl-xL expression. J Cerebr Blood F Met 26:708–721

    Article  CAS  Google Scholar 

  62. Fujinaka Y, Takane K, Yamashita H, Vasavada RC (2007) Lactogens promote beta cell survival through JAK2/STAT5 activation and Bcl-XL upregulation. J Biol Chem 282:30707–30717. doi:10.1074/jbc.M702607200

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The current research work was funded by Department of Science and Technology (DST), Government of India (GOI). Taranjeet Kaur, Rachana Mishra and Shaffi Manchanda are thankful to University Grants Commission (UGC), GOI for fellowship grant during the entire course of study. Harpal Singh and Anuradha Sharma are thankful to DST, GOI for fellowship grant. Muskan Gupta and Vedangana Saini are thankful to Council of Scientific and Industrial Research (CSIR), GOI for fellowship grant. Infrastructure provided by UGC, India under University with Potential for Excellence (UPE) and Centre with Potential for Excellence in Particular Area (CPEPA) schemes and Department of Biotechnology (DBT), India 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.

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  1. Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India

    Taranjeet Kaur, Harpal Singh, Shaffi Manchanda, Muskan Gupta, Vedangana Saini, Anuradha Sharma & Gurcharan Kaur

  2. Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. Wood St., Rm 578 MC 512, Chicago, IL, 60612, USA

    Rachana Mishra

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  1. Taranjeet Kaur
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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.

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Kaur, T., Singh, H., Mishra, R. et al. Withania somnifera as a potential anxiolytic and immunomodulatory agent in acute sleep deprived female Wistar rats. Mol Cell Biochem 427, 91–101 (2017). https://doi.org/10.1007/s11010-016-2900-1

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