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Bacopa monnieri extract improves novel object recognition, cell proliferation, neuroblast differentiation, brain-derived neurotrophic factor, and phosphorylation of cAMP response element-binding protein in the dentate gyrus

Abstract

Bacopa monnieri is a medicinal plant with a long history of use in Ayurveda, especially in the treatment of poor memory and cognitive deficits. In the present study, we hypothesized that Bacopa monnieri extract (BME) can improve memory via increased cell proliferation and neuroblast differentiation in the dentate gyrus. BME was administered to 7-week-old mice once a day for 4 weeks and a novel object recognition memory test was performed. Thereafter, the mice were euthanized followed by immuno-histochemistry analysis for Ki67, doublecortin (DCX), and phosphorylated cAMP response element-binding protein (CREB), and western blot analysis of brain-derived neurotrophic factor (BDNF). BME-treated mice showed moderate increases in the exploration of new objects when compared with that of familiar objects, leading to a significant higher discrimination index compared with vehicle-treated mice. Ki67 and DCX immunohistochemistry showed a facilitation of cell proliferation and neuroblast differentiation following the administration of BME in the dentate gyrus. In addition, administration of BME significantly elevated the BDNF protein expression in the hippocampal dentate gyrus, and increased CREB phosphorylation in the dentate gyrus. These data suggest that BME improves novel object recognition by increasing the cell proliferation and neuroblast differentiation in the dentate gyrus, and this may be closely related to elevated levels of BDNF and CREB phosphorylation in the dentate gyrus.

References

  1. 1.

    Khalaf-Nazzal R, Francis F. Hippocampal development-old and new findings. Neuroscience 2013; 248: 225–242.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Atri A, Sherman S, Norman KA, Kirchhoff BA, Nicolas MM, Greicius MD, Cramer SC, Breiter HC, Hasselmo ME, Stern CE. Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. Behav Neurosci 2004; 118(1): 223–236.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Hasselmo ME, McGaughy J. High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. Prog Brain Res 2004; 145: 207–231.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Buccafusco JJ, Letchworth SR, Bencherif M, Lippiello PM. Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance. Trends Pharmacol Sci 2005; 26(7): 352–360.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Levin ED, McClernon FJ, Rezvani AH. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 2006; 184(3–4): 523–539.

    CAS  Article  Google Scholar 

  6. 6.

    Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4(11): 1313–1317.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 1999; 2(3): 260–265.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Alam MJ, Kitamura T, Saitoh Y, Ohkawa N, Kondo T, Inokuchi K. Adult Neurogenesis Conserves Hippocampal Memory Capacity. J Neurosci 2018; 38(31): 6854–6863.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Aguiar S, Borowski T. Neuropharmacological review of the nootropic herb Bacopa monnieri. Rejuvenation Res 2013; 16(4): 313–326.

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Rastogi S, Pal R, Kulshreshtha DK. Bacoside A3—a triterpenoid saponin from Bacopa monniera. Phytochemistry 1994; 36(1): 133–137.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Garai S, Mahato SB, Ohtani K, Yamasaki K. Bacopasaponin D—a pseudojujubogenin glycoside from Bacopa monniera. Phytochemistry 1996; 43(2): 447–449.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Saraf MK, Anand A, Prabhakar S. Scopolamine induced amnesia is reversed by Bacopa monniera through participation of kinase-CREB pathway. Neurochem Res 2010; 35(2): 279–287.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Liu X, Yue R, Zhang J, Shan L, Wang R, Zhang W. Neuroprotective effects of bacopaside I in ischemic brain injury. Restor Neurol Neurosci 2013; 31(2): 109–123.

    CAS  PubMed  Google Scholar 

  14. 14.

    Pase MP, Kean J, Sarris J, Neale C, Scholey AB, Stough C. The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials. J Altern Complement Med 2012; 18(7): 647–652.

    PubMed  Article  Google Scholar 

  15. 15.

    Kumar S, Mondal AC. Neuroprotective, Neurotrophic and Anti-oxidative Role of Bacopa monnieri on CUS Induced Model of Depression in Rat. Neurochem Res 2016; 41(11): 3083–3094.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010; 8(6): e1000412.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Brown JP, Couillard-Després S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG. Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 2003; 467(1): 1–10.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, Bogdahn U, Winkler J, Kuhn HG, Aigner L. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci 2005; 21(1): 1–14.

    PubMed  Article  Google Scholar 

  19. 19.

    Rani A, Prasad S. A Special Extract of Bacopa monnieri (CDRI-08)-Restored Memory in CoCl2-Hypoxia Mimetic Mice Is Associated with Upregulation of Fmr-1 Gene Expression in Hippocampus. Evid Based Complement Alternat Med 2015; 2015: 347978.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Jung HY, Kim DW, Nam SM, Kim JW, Chung JY, Won MH, Seong JK, Yoon YS, Yoo DY, Hwang IK. Pyridoxine improves hippocampal cognitive function via increases of serotonin turnover and tyrosine hydroxylase, and its association with CB1 cannabinoid receptor-interacting protein and the CB1 cannabinoid receptor pathway. Biochim Biophys Acta Gen Subj 2017; 1861(12): 3142–3153.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. Academic Press, San Diego, 2001.

    Google Scholar 

  22. 22.

    Sairam K, Rao CV, Babu MD, Goel RK. Prophylactic and curative effects of Bacopa monniera in gastric ulcer models. Phytomedicine 2001; 8(6): 423–430.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Kumar V. Potential medicinal plants for CNS disorders: an overview. Phytother Res 2006; 20(12): 1023–1035.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Pandey SP, Singh HK, Prasad S. Alterations in Hippocampal Oxidative Stress, Expression of AMPA Receptor GluR2 Subunit and Associated Spatial Memory Loss by Bacopa monnieri Extract (CDRI-08) in Streptozotocin-Induced Diabetes Mellitus Type 2 Mice. PLoS One 2015; 10(7): e0131862.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Chaudhari KS, Tiwari NR, Tiwari RR, Sharma RS. Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer’s Disease. Ann Neurosci 2017; 24(2): 111–122.

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Saraf MK, Prabhakar S, Khanduja KL, Anand A. Bacopa monniera Attenuates Scopolamine-Induced Impairment of Spatial Memory in Mice. Evid Based Complement Alternat Med 2011; 2011: 236186.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, Nathan PJ. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl) 2001; 156(4): 481–484.

    CAS  Article  Google Scholar 

  28. 28.

    Peth-Nui T, Wattanathorn J, Muchimapura S, Tong-Un T, Piyavhatkul N, Rangseekajee P, Ingkaninan K, Vittaya-Areekul S. Effects of 12-Week Bacopa monnieri Consumption on Attention, Cognitive Processing, Working Memory, and Functions of Both Cholinergic and Monoaminergic Systems in Healthy Elderly Volunteers. Evid Based Complement Alternat Med 2012; 2012: 606424.

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Riedel G, Micheau J, Lam AG, Roloff EL, Martin SJ, Bridge H, de Hoz L, Poeschel B, McCulloch J, Morris RG. Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat Neurosci 1999; 2(10): 898–905.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Promsuban C, Limsuvan S, Akarasereenont P, Tilokskulchai K, Tapechum S, Pakaprot N. Bacopa monnieri extract enhances learning-dependent hippocampal long-term synaptic potentiation. Neuroreport 2017; 28(16): 1031–1035.

    PubMed  Article  Google Scholar 

  31. 31.

    Lindholm JS, Castrén E. Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. Front Behav Neurosci 2014; 8: 143.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Suzuki A, Fukushima H, Mukawa T, Toyoda H, Wu LJ, Zhao MG, Xu H, Shang Y, Endoh K, Iwamoto T, Mamiya N, Okano E, Hasegawa S, Mercaldo V, Zhang Y, Maeda R, Ohta M, Josselyn SA, Zhuo M, Kida S. Upregulation of CREB-mediated transcription enhances both short- and long-term memory. J Neurosci 2011; 31(24): 8786–8802.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Kida S, Serita T. Functional roles of CREB as a positive regulator in the formation and enhancement of memory. Brain Res Bull 2014; 105: 17–24.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Konar A, Gautam A, Thakur MK. Bacopa monniera (CDRI-08) Upregulates the Expression of Neuronal and Glial Plasticity Markers in the Brain of Scopolamine Induced Amnesic Mice. Evid Based Complement Alternat Med 2015; 2015: 837012.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Ortega-Martínez S. A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front Mol Neurosci 2015; 8: 46.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Hazra S, Kumar S, Saha GK, Mondal AC. Reversion of BDNF, Akt and CREB in Hippocampus of Chronic Unpredictable Stress Induced Rats: Effects of Phytochemical, Bacopa Monnieri. Psychiatry Investig 2017; 14(1): 74–80.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Preethi J, Singh HK, Venkataraman JS, Rajan KE. Standardised extract of Bacopa monniera (CDRI-08) improves contextual fear memory by differentially regulating the activity of histone acetylation and protein phosphatases (PP1α, PP2A) in hippocampus. Cell Mol Neurobiol 2014; 34(4): 577–589.

    PubMed  Article  Google Scholar 

  38. 38.

    Preethi J, Singh HK, Rajan KE. Possible Involvement of Standardized Bacopa monniera Extract (CDRI-08) in Epigenetic Regulation of reelin and Brain-Derived Neurotrophic Factor to Enhance Memory. Front Pharmacol 2016; 7: 166.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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Correspondence to Dae Won Kim.

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Kwon, H.J., Jung, H.Y., Hahn, K.R. et al. Bacopa monnieri extract improves novel object recognition, cell proliferation, neuroblast differentiation, brain-derived neurotrophic factor, and phosphorylation of cAMP response element-binding protein in the dentate gyrus. Lab Anim Res 34, 239–247 (2018). https://doi.org/10.5625/lar.2018.34.4.239

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Keywords

  • Bacopa monnieri extract
  • dentate gyrus
  • novel object recognition
  • neurogenesis
  • brain-derived neurotrophic factor