Cellular and Molecular Targets Underpinning Memory Enhancement by Ashwagandha

  • Arpita KonarEmail author
  • Mahendra K. Thakur


The search for therapeutic candidates of memory disorders including gene targets and compounds both synthetic and natural has been a prime arena of neurobiology research. Amongst suggested therapeutic compounds, several herbal products with a long history of use in Ayurveda have gained attention in modern medicine. Ashwagandha (Withania somnifera) also referred to as “Queen of Ayurveda” is at the zenith of Ayurvedic herbs owing to its tremendous potential to recover memory decline in aging and neurodegenerative pathologies as well as enhance basal memory function of healthy individuals. Despite such promising effects, limited mechanistic evidences have hindered its acceptance in modern medicine. However, technical advances in neuroscience research over the past decade have filled-in some gaps in understanding of molecular and mechanistic biology of Ashwagandha effects. In this chapter, we highlight the studies that have deciphered the cellular and molecular mechanisms of memory enhancing potential of Ashwagandha in various disease models. Cellular targets of Ashwagandha include (i) activation of antioxidant defence system rescuing nerve cells from apoptosis, oxidative stress and DNA damage, (ii) induction of cholinergic system and (iii) up-regulation of memory linked neuroplasticity genes and neuronal arborisation. All of these molecular effects translate into increase in memory. Such multiple-module action has intrigued research to unravel upstream master regulators of Ashwagandha effects on gene expression, cell physiology and behaviour.


Ashwagandha Anti-oxidant Induction of cholinergic system Enhance memory function Multiple-module action 



The work cited in this article from authors’ laboratory has been supported by grants from the Department of Science and Technology (SR/SO/HS-54/2008) and Department of Biotechnology (BT/PR3996/MED/97/57/2011), Government of India.


  1. 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 145:431–441CrossRefPubMedGoogle Scholar
  2. Baitharu I, Jain V, Deep SN, Shroff S, Sahu JK, Naik PK, Ilavazhagan G (2014) Withanolide A prevents neurodegeneration by modulating hippocampal glutathione biosynthesis during hypoxia. PLoS One 9:e105311CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bano D, Agostini M, Melino G, Nicotera P (2011) Ageing, neuronal connectivity and brain disorders: an unsolved ripple effect. Mol Neurobiol 43:124–130CrossRefPubMedGoogle Scholar
  4. Bartsch T, Deuschl G (2010) Transient global amnesia: functional anatomy and clinical implications. Lancet Neurol 9:205–214CrossRefPubMedGoogle Scholar
  5. Bekinschtein P, Cammarota M, Medina JH (2013) BDNF and memory processing. Neuropharmacol 76:677–683CrossRefGoogle Scholar
  6. Ben Achour S, Pascual O (2010) Glia: the many ways to modulate synaptic plasticity. Neurochem Int 57:440–445CrossRefPubMedGoogle Scholar
  7. Bhattarai JP, Ah Park S, Han SK (2010) The methanolic extract of Withania somnifera ACTS on GABAA receptors in gonadotropin releasing hormone (GnRH) neurons in mice. Phytother Res 24:1147–1150PubMedGoogle Scholar
  8. Bhattarai JP, Park SJ, Han SK (2013) Potentiation of NMDA receptors by Withania somnifera on hippocampal CA1 pyramidal neurons. Am J Chin Med 41:503–513CrossRefPubMedGoogle Scholar
  9. Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, Panja D, Schubert M, Soule J, Tiron A, Wibrand K (2009) The Arc of synaptic memory. Exp Brain Res 200:125–140CrossRefPubMedPubMedCentralGoogle Scholar
  10. Budson AE, Price BH (2005) Memory dysfunction. N Engl J Med 352:692–699CrossRefPubMedGoogle Scholar
  11. Candelario M, Cuellar E, Reyes-Ruiz JM, Darabedian N, Feimeng Z, Miledi R, Russo-Neustadt A, Limon A (2015) Direct evidence for GABAergic activity of Withania somnifera on mammalian ionotropic GABAA and GABAρ receptors. J Ethnopharmacol 171:264–272CrossRefPubMedGoogle Scholar
  12. Cavallaro S, D’Agata V, Manickam P, Dufour F, Alkon DL (2002) Memory-specific temporal profiles of gene expression in the hippocampus. Proc Natl Acad Sci U S A99:16279–16284CrossRefGoogle Scholar
  13. Cingolani LA, Goda Y (2008) Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9:344–356CrossRefPubMedGoogle Scholar
  14. 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 6:1–8CrossRefGoogle Scholar
  15. Di Carlo M, Giacomazza D, Picone P, Nuzzo D, San Biagio PL (2012) Are oxidative stress and mitochondrial dysfunction the key players in the neurodegenerative diseases? Free Radic Res 46:1327–1338CrossRefPubMedGoogle Scholar
  16. Gautam A, Kaul SC, Thakur MK (2015) Alcoholic extract of Ashwagandha leaves protects against amnesia by regulation of Arc function. Mol Neurobiol 53:1760–1769CrossRefPubMedGoogle Scholar
  17. Gautam A, Wadhwa R, Thakur MK (2013) Involvement of hippocampal Arc in amnesia and its recovery by alcoholic extract of Ashwagandha leaves. Neurobiol Learn Mem 106:177–184CrossRefPubMedGoogle Scholar
  18. Gold PE (2006) The many faces of amnesia. Learn Mem 13:506–514CrossRefPubMedGoogle Scholar
  19. Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20:3993–4001PubMedGoogle Scholar
  20. Harada A, Teng J, Takei Y, Oguchi K, Hirokawa N (2002) MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction. J Cell Biol 158:541–549CrossRefPubMedPubMedCentralGoogle Scholar
  21. Havekes R, Vecsey CG, Abel T (2012) The impact of sleep deprivation on neuronaland glial signaling pathways important for memory and synaptic plasticity. Cell Signal 24:1251–1260CrossRefPubMedPubMedCentralGoogle Scholar
  22. Holger J (2013) Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci 15:445–454Google Scholar
  23. Hubka P (2006) Neural network plasticity, BDNF and behavioral interventions in Alzheimer’s disease. Bratisl Lek Listy 107:395–401PubMedGoogle Scholar
  24. Igaz LM, Bekinschtein P, Vianna MM, Izquierdo I, Medina JH (2004) Gene expression during memory formation. Neurotox Res 6:189–204CrossRefPubMedGoogle Scholar
  25. Jansen RL, Brogan B, Whitworth AJ, Okello EJ (2014) Effects of five Ayurvedic herbs on locomotor behaviour in a Drosophila melanogaster Parkinson’s disease model. Phytother Res 28:1789–1795CrossRefPubMedPubMedCentralGoogle Scholar
  26. Jayaprakasam B, Padmanabhan K, Nair MG (2010) Withanamides in Withania somnifera fruit protect PC-12 cells from beta-amyloid responsible for Alzheimer’s disease. Phytother Res 24:859–863PubMedGoogle Scholar
  27. Johnson JL, Huang W, Roman G, Costa-Mattioli M (2015) TORC2: a novel target for treating age-associated memory impairment. Sci Rep 5:15193CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kidd PM (2008) Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev 13:85–115PubMedGoogle Scholar
  29. Klinkenberg I, Blokland A (2010) The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 34:1307–1350CrossRefPubMedGoogle Scholar
  30. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One 6:e27265CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kuboyama T, Tohda C, Komatsu K (2005) Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol 144:961–971CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kuboyama T, Tohda C, Komatsu K (2006) Withanoside IV and its active metabolite, sominone, attenuate Abeta(25-35)-induced neurodegeneration. Eur J Neurosci 23:1417–1426CrossRefPubMedGoogle Scholar
  33. Kuboyama T, Tohda C, Komatsu K (2014) Effects of Ashwagandha roots of Withania somnifera on neurodegenerative diseases. Biol Pharm Bull 37:892–897CrossRefPubMedGoogle Scholar
  34. Kulkarni SK, Dhir A (2008) Withania somnifera: an Indian ginseng. Prog Neuropsychopharmacol Biol Psychiatry 32:1093–1105CrossRefPubMedGoogle Scholar
  35. Kumar GP, Khanum F (2012) Neuroprotective potential of phytochemicals. Pharmacogn Rev 6:81–90CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kumar S, Seal CJ, Howes MJ, Kite GC, Okello EJ (2010) In vitro protective effects of Withania somnifera (L.) dunal root extract against hydrogen peroxideand beta-amyloid (1-42)-induced cytotoxicity in differentiated PC12 cells. Phytother Res 24:1567–1574CrossRefPubMedGoogle Scholar
  37. Kurapati KR, Atluri VS, Samikkannu T, Nair MP (2013) Ashwagandha (Withania somnifera) reverses beta-amyloid1-42 induced toxicity in human neuronal cells:implications in HIV-associated neurocognitive disorders (HAND). PLoS One 8:e77624CrossRefPubMedPubMedCentralGoogle Scholar
  38. Leal G, Comprido D, Duarte CB (2013) BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76:639–656CrossRefPubMedGoogle Scholar
  39. Lee Y, Silva A (2009) The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10:126–140CrossRefPubMedPubMedCentralGoogle Scholar
  40. Liu LF, Durairajan SS, Lu JH, Ko I, Li M (2012) In vitro screening on amyloid precursor protein modulation of plants used in Ayurvedic and traditional Chinese medicine for memory improvement. J Ethnopharmacol 141:754–760CrossRefPubMedGoogle Scholar
  41. Manjunath MJ, Muralidhara (2013) Effect of Withania somnifera supplementation on rotenone-induced oxidative damage in cerebellum and striatum of the male mice brain. Am J Chin Med 41:503–513CrossRefGoogle Scholar
  42. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639CrossRefPubMedPubMedCentralGoogle Scholar
  43. McKay G, Kopelman MD (2009) Psychogenic amnesia: when memory complaints are medically unexplained. Adv Psychiatr Treat 15:152–158CrossRefGoogle Scholar
  44. McKinney M, Jacksonville MC (2005) Brain cholinergic vulnerability: relevance to behavior and disease. Biochem Pharmacol 70:1115–1124CrossRefPubMedGoogle Scholar
  45. Mishra LC, Singh BB, Dagenais S (2000) Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 5:334–346PubMedGoogle Scholar
  46. Modak M, Dixit P, Londhe J, Ghaskadbi S, Paul ADT (2007) Indian herbs and herbal drugs used for the treatment of diabetes. J Clin Biochem Nutr 40:163–173CrossRefPubMedPubMedCentralGoogle Scholar
  47. Morrison JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250PubMedPubMedCentralGoogle Scholar
  48. RajaSankar S, Manivasagam T, Sankar V, Prakash S, Muthusamy R, Krishnamurti A, Surendran S (2009) Withania somnifera root extract improves catecholamines and physiological abnormalities seen in a Parkinson’s disease model mouse. J Ethnopharmacol 125:369–373CrossRefPubMedGoogle Scholar
  49. Sankar SR, Manivasagam T, Krisnamurt A, Ramanathan M (2007) The neuroprotective effect of Withania somnifera root extract in MPTP-intoxicated mice: An analysis of behavioural and biochemical variables. Cell Mol Biol Lett 12:473–481CrossRefPubMedGoogle Scholar
  50. Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563CrossRefPubMedGoogle Scholar
  51. Schulze ET, Geary EK, Susmaras MT, Paliga JT, Maki PM, Little DM (2011) Anatomical correlates of age-related working memory declines. J Aging Res 1–9Google Scholar
  52. Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, Khanna P, Jain SC, Thakur SS, Ravindranath V (2012) Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor related protein in liver. Proc Natl Acad Sci USA 109:3510–3515CrossRefPubMedPubMedCentralGoogle Scholar
  53. Shukla KK, Mahdi AA, Mishra V, Rajender S, Sankhwar SN, Patel D, Das M (2011) Withania somnifera improves semen quality by combating oxidative stress and cell death and improving essential metal concentrations. Reprod Biomed Online 22:421–427CrossRefPubMedGoogle Scholar
  54. Silva AF, Aguiar MS, Carvalho OS, Santana Lde N, Franco EC, Lima RR, Siqueira NV, Feio RA, Faro LR, Gomes-Leal W (2013) Hippocampal neuronal loss, decreased GFAP immunoreactivity and cognitive impairment following experimental intoxication of rats with aluminum citrate. Brain Res 1491:23–33CrossRefPubMedGoogle Scholar
  55. Singh N, Bhalla M, de Jager P, Gilca M (2011) An overview on ashwagandha: a Rasayana (rejuvenator) of Ayurveda. Afr J Tradit Complement Altern Med 8:208–213PubMedPubMedCentralGoogle Scholar
  56. Singh RH, Narsimhamurthy K, Singh G (2008) Neuronutrient impact of Ayurvedic Rasayana therapy in brain aging. Biogerontol 9:369–374CrossRefGoogle Scholar
  57. Soman S, Korah PK, Jayanarayanan S, Mathew J, Paulose CS (2012) Oxidative stress induced NMDA receptor alteration leads to spatial memory deficits in temporal lobe epilepsy: ameliorative effects of Withania somnifera and Withanolide A. Neurochem Res 37:1915–1927CrossRefPubMedGoogle Scholar
  58. Tohda C (2008) Overcoming several neurodegenerative diseases by traditional medicines: the development of therapeutic medicines and unravelling pathophysiological mechanisms. Yakugaku Zasshi 128:1159–1167CrossRefPubMedGoogle Scholar
  59. Tohda C, Joyashiki E (2009) Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor, RET. Br J Pharmacol 157:1427–1440CrossRefPubMedPubMedCentralGoogle Scholar
  60. Ven Murthy MR, Ranjekar PK, Ramassamy C, Deshpande M (2010) Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha. Cent Nerv Syst Agents Med Chem 10:238–246CrossRefPubMedGoogle Scholar
  61. Waterhouse EG, Xu B (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci 42:81–89CrossRefPubMedPubMedCentralGoogle Scholar
  62. Winters M (2006) Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology. Altern Med Rev 11:269–277PubMedGoogle Scholar
  63. Yamada K, Nabeshima T (2003) Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 91:267–270CrossRefPubMedGoogle Scholar
  64. Young EJ, Briggs SB, Miller CA (2015) The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use. CNS Neurol Disord Drug Targets 14:731–737CrossRefPubMedPubMedCentralGoogle Scholar
  65. Zhao J, Nakamura N, Hattori M, Kuboyama T, Tohda C, Komatsu K (2002) Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem Pharm Bull 50:760–765CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.CSIR-Institute of Genomics & Integrative BiologyNew DelhiIndia
  2. 2.Biochemistry and Molecular Biology Laboratory, Brain Research Centre, Department of ZoologyBanaras Hindu UniversityVaranasiIndia

Personalised recommendations