Bacopa monnieri supplementation has no effect on serum brain-derived neurotrophic factor levels but beneficially modulates nuclear factor kappa B and cyclic AMP response element-binding protein levels in healthy elderly subjects

Andrew P. Keegan^{1 *}, Con Stough², Daniel Paris¹, Cheryl A. Luis¹, Laila Abdullah¹, Ghania Ait-ghezala¹, Fiona Crawford¹, Michael Mullan¹

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¹ The Roskamp Institute, Sarasota, Florida, United States of America

² Swinburne Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia

JCTR 2023, 9(1), 50–58; https://doi.org/10.18053/jctres.09.202301.007

Submitted: 17 September 2022 | Revised: 23 November 2022 | Accepted: 23 November 2022 | Published: 17 January 2023

© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )

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Abstract

Background and aim: Bacopa monnieri is an Ayurvedic herb that has been used for multiple conditions, most notably to augment cognition, particularly memory and attention. Multiple mechanisms, including raising brain-derived neurotrophic factor (BDNF), have been proposed and investigated in animal models that require translational studies in humans.

Methods: Bacopa was administered in an open-labeled study to cognitively healthy controls over a three-month period. Cognition and mood were assessed using the Montreal Cognitive Assessment (MoCA) and Geriatric Depression Scale (GDS) at the baseline and 3-month visit. Labs were assessed for safety and serum levels of mature (mBDNF) and proBDNF were quantified. In a subset of subjects, intracellular signaling processes were assessed using Western blot analysis.

Results: Bacopa was provided to 35 subjects and was well-tolerated except for 4 (11%) subjects who early terminated due to known, reversible, gastrointestinal side effects (i.e. nausea, diarrhea). Over the 3 months, the GDS and the total MoCA did not significantly change, however, the delayed-recall subscale significantly improved (baseline: 3.8 ± 1.2, 3-months: 4.3 ± 0.9; p = 0.032). Serum mBDNF and proBDNF levels did not significantly change. Cyclic AMP response element-binding protein (CREB) phosphorylation significantly increased (p = 0.028) and p65 nuclear factor kappa B (NF-κB) phosphorylation significantly decreased (p = 0.030).

Conclusion: These results suggest Bacopa may exert an anti-inflammatory effect via NF-κB and improve intracellular signaling processes associated with synaptogenesis (CREB). Future placebo-controlled studies are recommended.

Relevance for patients: Bacopa monnieri will require larger, blinded trials to better understand potential mechanisms, interactions, and utilization.

Keywords

Biomarkers

Bacopa

Brain-derived neurotrophic factor

Conflict of interest

The authors declare no conflicts of interest.

References

[1] Mathur D, Goyal K, Koul V, Anand A. The Molecular Links of Re-Emerging Therapy: A Review of Evidence of Brahmi (Bacopa monniera). Front Pharmacol 2016;7:44.

[2] Chaudhari KS, Tiwari NR, Tiwari RR, Sharma RS. Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer’s Disease. Ann Neurosci 2017;24:111-22.

[3] Aguiar S, Borowski T. Neuropharmacological Review of the Nootropic Herb Bacopa monnieri. Rejuvenation Res 2013;16:313-26.

[4] Stough C, Singh H, Zangara A. Mechanisms, Efficacy, and Safety of Bacopa monnieri (Brahmi) for Cognitive and Brain Enhancement. Evid Based Complement Alternat Med 2015;2015:717605.

[5] Simpson T, Pase M, Stough C. Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain. Evid Based Complement Alternat Med 2015;2015:615384.

[6] Brimson JM, Brimson S, Prasanth MI, Thitilertdecha P, Malar DS, Tencomnao T. The Effectiveness of Bacopa monnieri (Linn.) Wettst. As a Nootropic, Neuroprotective, or Antidepressant Supplement: Analysis of the Available Clinical Data. Sci Rep 2021;11:596.

[7] Kongkeaw C, Dilokthornsakul P, Thanarangsarit P, Limpeanchob N, Scholfield CN. Meta-Analysis of Randomized Controlled Trials on Cognitive Effects of Bacopa monnieri Extract. J Ethnopharmacol 2014;151:528-35.

[8] Calabrese C, Gregory WL, Leo M, Kraemer D, Bone K, Oken B. Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: ARandomized, Double-Blind, Placebo-Controlled Trial. J Alternat Complement Med 2008;14:707-13.

[9] Stough CK, Pase MP, Cropley V, Myers S, Nolidin K, King R, et al. A Randomized Controlled Trial Investigating the Effect of Pycnogenol and Bacopa CDRI08 Herbal Medicines on Cognitive, Cardiovascular, and Biochemical Functioning in Cognitively Healthy Elderly People: The Australian Research Council Longevity Intervention (ARCLI) Study Protocol (ANZCTR12611000487910). Nutr J 2012;11:11.

[10] Mizui T, Ishikawa Y, Kumanogoh H, Kojima M. Neurobiological Actions by Three Distinct Subtypes of Brain-Derived Neurotrophic Factor: Multi-Ligand Model of Growth Factor Signaling. Pharmacol Res 2016;105:93-8.

[11] Küster OC, Laptinskaya D, Fissler P, Schnack C, Zügel M, Nold V, et al. Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway. J Alzheimers Dis 2017;59:1097-111.

[12] Allard JS, Ntekim O, Johnson SP, Ngwa JS, Bond V, Pinder D, et al. APOEε4 Impacts Up-Regulation of BrainDerived Neurotrophic Factor after a Six-Month Stretch and Aerobic Exercise Intervention in Mild Cognitively Impaired Elderly African Americans: A Pilot Study. Exp Gerontol 2017;87:129-36.

[13] Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM. Serum BDNF Concentrations as Peripheral Manifestations of Depression: Evidence from a Systematic Review and Meta-Analyses on 179 Associations (N=9484). Mol Psychiatry 2014;19:791-800.

[14] Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter ML. BDNF as a Biomarker for Successful Treatment of Mood Disorders: A Systematic & Quantitative Meta-Analysis. J Affect Disord 2015;1%15. 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.

[16] Micheli L, Spitoni S, Di Cesare Mannelli L, Bilia AR, Ghelardini C, Pallanti S. Bacopa monnieri as Augmentation Therapy in the Treatment of Anhedonia, Preclinical and Clinical Evaluation. Phytother Res 2020;34:2331-40.

[17] Banerjee R, Hazra S, Ghosh AK, Mondal AC. Chronic Administration of Bacopa monniera Increases BDNF Protein and mRNA Expressions: A Study in Chronic Unpredictable Stress Induced Animal Model of Depression. Psychiatry Investig 2014;11:297-306.

[18] 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;34:577-89.

[19] Kwon HJ, Jung HY, Hahn KR, Kim W, Kim JW, Yoo DY, 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 2018;34:239-47.

[20] Le XT, Pham HT, Do PT, Fujiwara H, Tanaka K, Li F, et al. Bacopa monnieri Ameliorates Memory Deficits in Olfactory Bulbectomized Mice: Possible Involvement of Glutamatergic and Cholinergic Systems. Neurochem Res 2013;38:2201-15.

[21] Costantini E, Jarlapoodi S, Serra F, Aielli L, Khan H, Belwal T, et al. Neuroprotective Potential of Bacopa monnieri: Modulation of Inflammatory Signals. CNS Neurol Disord Drug Targets 2022;21:441-51.

[22] Viji V, Shobha B, Kavitha SK, Ratheesh M, Kripa K, Helen A. Betulinic Acid Isolated from Bacopa monniera (L.) Wettst Suppresses Lipopolysaccharide Stimulated Interleukin-6 Production through Modulation of Nuclear Factor-κB in Peripheral Blood Mononuclear Cells. Int Immunopharmacol 2010;10:843-9.

[23] 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.

[24] Zu X, Zhang M, Li W, Xie H, Lin Z, Yang N, et al. Antidepressant-like Effect of Bacopaside I in Mice Exposed to Chronic Unpredictable Mild Stress by Modulating the Hypothalamic-Pituitary-Adrenal Axis Function and Activating BDNF Signaling Pathway. Neurochem Res 2017;42:3233-44.

[25] 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;14:74-80.

[26] 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.

[27] McPhee GM, Downey LA, Wesnes KA, Stough C. The Neurocognitive Effects of Bacopa monnieri and Cognitive Training on Markers of Brain Microstructure in Healthy Older Adults. Front Aging Neurosci 2021;13:638109.

[28] Weathers FW, Blake DD, Schnurr PP, Kaloupek DG, Marx BP, Keane TM. The Life Events Checklist for DSM5 (LEC-5)-Standard. Available from: https://www.ptsd. va.gov/professional/assessment/te-measures/life_events_ checklist.asp [Last accessed on 2021 Dec 31].

[29] Yesavage JA. Geriatric Depression Scale. Psychopharmacol Bull 1988;24:709-10.

[30] Polacchini A, Metelli G, Francavilla R, Baj G, Florean M, Mascaretti LG, et al. AMethod for Reproducible Measurements of Serum BDNF: Comparison of the Performance of Six Commercial Assays. Sci Rep 2015;5:17989.

[31] Paris D, Ait-Ghezala G, Bachmeier C, Laco G, BeaulieuAbdelahad D, Lin Y, et al. The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation. J Biol Chem 2014;289:33927-44.

[32] Paris D, Beaulieu-Abdelahad D, Abdullah L, Bachmeier C, Ait-Ghezala G, Reed J, et al. Anti-inflammatory Activity of Anatabine Via Inhibition of STAT3 Phosphorylation. Eur J Pharmacol 2013;698:145-53.

[33] Fahnestock M. Brain-Derived Neurotrophic Factor: The Link Between Amyloid-B and Memory Loss. Future Neurol 2011;6:627-39.

[34] Lim YY, Rainey-Smith S, Lim Y, Laws SM, Gupta V, Porter T, et al. BDNF Val66Met in Preclinical Alzheimer’s Disease is Associated with Short-Term Changes in Episodic Memory and Hippocampal Volume but Not Serum mBDNF. Int Psychogeriatr 2017;29:1825-34.

[35] Sangiovanni E, Brivio P, Dell’Agli M, Calabrese F. Botanicals as Modulators of Neuroplasticity: Focus on BDNF. Neural Plast 2017;2017:5965371.

[36] Martin A, Stillman J, Miguez MJ, McDaniel HR, Konefal J, Woolger JM, et al. The Effect of Dietary Supplementation on Brain-Derived Neurotrophic Factor and Cognitive Functioning in Alzheimer’s Dementia. J Clin Transl Res 2018;3:337-43.

[37] Sartorius A, Hellweg R, Litzke J, Vogt M, Dormann C, Vollmayr B, et al. Correlations and Discrepancies Between Serum and Brain Tissue Levels of Neurotrophins after Electroconvulsive Treatment in Rats. Pharmacopsychiatry 2009;42:270-6.

[38] Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, et al. Blood BDNF Concentrations Reflect Brain-Tissue BDNF Levels Across Species. Int J Neuropsychopharmacol 2011;14:347-53.

[39] Fukuchi M, Saito R, Maki S, Hagiwara N, Nakajima Y, Mitazaki S, et al. Visualization of Activity-Regulated BDNF Expression in the Living Mouse Brain Using NonInvasive Near-Infrared Bioluminescence Imaging. Mol Brain 2020;13:122.

[40] Wen AY, Sakamoto KM, Miller LS. The Role of the Transcription Factor CREB in Immune Function. J Immunol 2010;185:6413-9.

[41] Medunjanin S, Schleithoff L, Fiegehenn C, Weinert S, Zuschratter W, Braun-Dullaeus RC. GSK-3β Controls NFkappaB Activity Via IKKγ/NEMO. Sci Rep 2016;6:38553.

[42] Abd-Ellah A, Voogdt C, Krappmann D, Möller P, Marienfeld RB. GSK3β Modulates NF-κB Activation and RelB Degradation through Site-Specific Phosphorylation of BCL10. Sci Rep 2018;8:1352.

[43] Basheer A, Agarwal A, Mishra B, Gupta A, Srivastava MV, Kirubakaran R, et al. Use of Bacopa monnieri in the Treatment of Dementia Due to Alzheimer Disease: Systematic Review of Randomized Controlled Trials. Interact J Med Res 2022;11:e38542.

[44] Prabhakar S, Vishnu VY, Modi M, Mohanty M, Sharma A, Medhi B, et al. Efficacy of Bacopa monnieri (Brahmi) and Donepezil in Alzheimer’s Disease and Mild Cognitive Impairment: A Randomized Double-Blind Parallel Phase 2b Study. Ann Indian Acad Neurol 2020;23:767-73.

[45] Leyhe T, Stransky E, Eschweiler GW, Buchkremer G, Laske C. Increase of BDNF Serum Concentration During Donepezil Treatment of Patients with Early Alzheimer’s Disease. Eur Arch Psychiatry Clin Neurosci 2008;258:124-8.

[46] Invernizzi S, Loureiro IS, Arachchige KG, Lefebvre L. LateLife Depression, Cognitive Impairment, and Relationship with Alzheimer’s Disease. Dement Geriatr Cogn Disord 2022;50:414-24.

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