Abstract
Millions of individuals with active TB do not receive recommended treatments, and instead may use botanicals, or use botanicals concurrently with established treatments. Many botanicals protect against oxidative stress, but this can interfere with redox-dependent activation of isoniazid and other prodrugs used for prophylaxis and treatment of TB, as suggested by results of a recent clinical trial of the South African botanical Sutherlandia frutescens (L.) R. Br. (Sutherlandia). Here we provide a brief summary of Sutherlandia’s effects upon rodent microglia and neurons relevant to tuberculosis of the central nervous system (CNS-TB). We have observed that ethanolic extracts of Sutherlandia suppress production of reactive oxygen species (ROS) in rat primary cortical neurons stimulated by NMDA and also suppress LPS- and interferon γ (IFNγ)-induced ROS and nitric oxide (NO) production by microglial cells. Sutherlandia consumption mitigates microglial activation in the hippocampus and striatum of ischemic brains of mice. RNAseq analysis indicates that Sutherlandia suppresses gene expression of oxidative stress, inflammatory signaling and toll-like receptor pathways that can reduce the host’s immune response to infection and reactivation of latent Mycobacterium tuberculosis. As a precautionary measure, we recommend that individuals receiving isoniazid for pulmonary or cerebral TB, be advised not to concurrently use botanicals or dietary supplements having antioxidant activity.
Similar content being viewed by others
References
Africa, L. D., & Smith, C. (2015). Sutherlandia frutescens may exacerbate HIV-associated neuroinflammation. Journal of Negative Results in Biomedicine, 14, 14.
Baulard, A. R., Betts, J. C., et al. (2000). Activation of the pro-drug ethionamide is regulated in mycobacteria. Journal of Biological Chemistry, 275(36), 28326–28331.
Block, M. L., Zecca, L., et al. (2007). Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Reviews Neuroscience, 8(1), 57–69.
Brown, G. C., & Neher, J. J. (2010). Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Molecular Neurobiology, 41(2–3), 242–247.
Calabrese, V., Cornelius, C., et al. (2009). Nitric oxide in cell survival: A janus molecule. Antioxidants and Redox Signaling, 11(11), 2717–2739.
Chin, J. H., & Mateen, F. J. (2013). Central nervous system tuberculosis: Challenges and advances in diagnosis and treatment. Current Infectious Disease Reports, 15, 631–635.
Chuang, D. Y., Cui, J., et al. (2014). Dietary Sutherlandia and elderberry mitigate cerebral ischemia-induced neuronal damage and attenuate p47phox and phospho-ERK1/2 expression in microglial cells. ASN Neuro, 6(6), 1–14.
Davids, D., Blouws, T., et al. (2014). Traditional health practitioners’ perceptions, herbal treatment and management of HIV and related opportunistic infections. Journal of Ethnobiology and Ethnomedicine, 10(1), 1–14.
Fernandes, A. C., Cromarty, A. D., Albrecht, C., & van Rensburg, C. E. (2004). The antioxidant potential of Sutherlandia frutescens. Journal of Ethnopharmacology, 95, 1–5.
Francisco, N. M., Hsu, N. J., et al. (2015). TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. Journal of Neuroinflammation, 12, 125.
Graeber, M. B., & Streit, W. J. (2010). Microglia: Biology and pathology. Acta Neuropathologica, 119(1), 89–105.
Isabel, B. E., & Rogelio, H. P. (2014). Pathogenesis and immune response in tuberculous meningitis. The Malaysian Journal of Medical Sciences: MJMS, 21(1), 4–10.
Jiang, J., Chuang, D. Y., et al. (2014). Sutherlandia frutescens ethanol extracts inhibit oxidative stress and inflammatory responses in neurons and microglial cells. PLoS One, 9(2), e89748.
John, C. C., Carabin, H., et al. (2015). Global research priorities for infections that affect the nervous system. Nature, 527(7578), S178–S186.
Katerere, D. R., & Eloff, J. N. (2005). Antibacterial and antioxidant activity of Sutherlandia frutescens (Fabaceae), a reputed anti-HIV/AIDS phytomedicine. Phytotherapy Research, 19, 779–781.
Kumar, A., Farhana, A., et al. (2011). Redox homeostasis in mycobacteria: The key to tuberculosis control? Expert Reviews in Molecular Medicine, 13, e39.
Lu, Y., Starkey, N., et al. (2015). Inhibition of Hedgehog-signaling driven genes in prostate cancer cells by Sutherlandia frutescens extract. PLoS One, 10(12), e0145507.
Mishra, B. B., Rathinam, V. A., et al. (2013). Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta. Nature Immunology, 14(1), 52–60.
Olin, M. R., Armien, A. G., et al. (2008). Role of nitric oxide in defense of the central nervous system against Mycobacterium tuberculosis. Journal of Infectious Diseases, 198(6), 886–889.
Pacher, P., Beckman, J. S., et al. (2007). Nitric oxide and peroxynitrite in health and disease. Physiological Reviews, 87(1), 315–424.
Qian, L., & Flood, P. M. (2008). Microglial cells and Parkinson’s disease. Immunologic Research, 41(3), 155–164.
Randall, P. J., Hsu, N. J., et al. (2015). Mycobacterium tuberculosis infection of the ‘non-classical immune cell’. Immunology and Cell Biology, 93(9), 789–795.
Rapanoel, H. A., Mazandu, G. K., et al. (2013). Predicting and analyzing interactions between Mycobacterium tuberculosis and its human host. PLoS One, 8(7), e67472.
Rock, R. B., Olin, M., Baker, C. A., Molitor, T. W., & Peterson, P. K. (2008). Central nervous system tuberculosis: Pathogenesis and clinical aspects. Clinical Microbiology Reviews, 21(2), 243–261. (table of contents).
Rogers, J., Mastroeni, D., et al. (2007). Neuroinflammation in Alzheimer’s disease and Parkinson’s disease: Are microglia pathogenic in either disorder? International Review of Neurobiology, 82, 235–246.
Saenz, B., Hernandez-Pando, R., et al. (2013). The dual face of central nervous system tuberculosis: A new Janus Bifrons? Tuberculosis (Edinb), 93(2), 130–135.
Singh, R., Manjunatha, U., et al. (2008). PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science, 322(5906), 1392–1395.
Streit, W. J. (2010). Microglial activation and neuroinflammation in Alzheimer’s disease: A critical examination of recent history. Frontiers in Aging Neuroscience, 2, 22.
Sutherlandia.org. (2016). Sutherlandia.org. http://sutherlandia.org/index.html.
Thwaites, G. E. & Schoeman J. F. (2009). Update on tuberculosis of the central nervous system: Pathogenesis, diagnosis, and treatment. Clinics in Chest Medicine, 30(4), 745–754, ix.
Timmins, G. S., & Deretic, V. (2006). Mechanisms of action of isoniazid. Molecular Microbiology, 62(5), 1220–1227.
Timmins, G. S., Master, S., et al. (2004a). Nitric oxide generated from isoniazid activation by KatG: Source of nitric oxide and activity against Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 48(8), 3006–3009.
Timmins, G. S., Master, S., et al. (2004b). Requirements for nitric oxide generation from isoniazid activation in vitro and inhibition of mycobacterial respiration in vivo. Journal of Bacteriology, 186(16), 5427–5431.
Tobwala, S., Fan, W., Hines, C. J., Folk, W. R., & Ercal, N. (2014). Antioxidant potential of Sutherlandia frutescens and its protective effects against oxidative stress in various cell cultures. BMC Complementary Alternative Medicine, 14, 271.
Tsang, A. H., & Chung, K. K. (2009). Oxidative and nitrosative stress in Parkinson’s disease. Biochimica et Biophysica Acta (BBA), 1792(7), 643–650.
van Wyk, B. E., & Albrecht, C. (2008). A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutescens (Fabaceae). Journal of Ethnopharmacology, 119(3), 620–629.
Vilcheze, C., & Jacobs, W. R, Jr. (2007). The mechanism of isoniazid killing: Clarity through the scope of genetics. Annual Review of Microbiology, 61, 35–50.
Voskuil, M. I., Bartek, I. L., et al. (2011). The response of mycobacterium tuberculosis to reactive oxygen and nitrogen species. Frontiers in Microbiology, 2, 105.
WHO. (2013). Traditional Medicine Strategy 2014-2023. Geneva: World Health Organization.
WHO. (2015). Recommendation on 36 months isoniazid preventive therapy to adults and adolescents living with HIV in resource-constrained and high TB- and HIV-prevalence settings: 2015 Update. Geneva.
WHO. (2015b). Global Tuberculosis Report 2015. Geneva: World Health Organization.
Wilson, D., Goggin, K., et al. (2015). Consumption of Sutherlandia frutescens by HIV-Seropositive South African Adults: An adaptive double-blind randomized placebo controlled trial. PLoS ONE, 10(7), e0128522.
Yang, C. S., Lee, H. M., et al. (2007). Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis-induced pro-inflammatory response in murine microglia. Journal of Neuroinflammation, 4, 27.
Yang, C. S., Yuk, J. M., et al. (2009). The role of nitric oxide in mycobacterial infections. Immune Network, 9(2), 46–52.
Acknowledgments
We thank members of the MU Center for Botanical Interaction Studies for advice and technical assistance. Financial support was provided by Grant P50AT006273 from the National Center for Complementary and Integrative Health (NCCIH) and the Office of Dietary Supplements (ODS) and the University of Missouri. The contents are solely the responsibility of the authors and do not necessarily reflect the views of the sponsors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Folk, W.R., Smith, A., Song, H. et al. Does Concurrent Use of Some Botanicals Interfere with Treatment of Tuberculosis?. Neuromol Med 18, 483–486 (2016). https://doi.org/10.1007/s12017-016-8402-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-016-8402-1