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Journal of Physiology and Biochemistry

, Volume 74, Issue 4, pp 539–547 | Cite as

Sceletium tortuosum may delay chronic disease progression via alkaloid-dependent antioxidant or anti-inflammatory action

  • A.C. Bennett
  • A. Van Camp
  • V. López
  • C. SmithEmail author
Original Article

Abstract

The link between obesity-induced systemic inflammation and decreased insulin signalling is well-known. It is also known that peripherally produced inflammatory cytokines can cross the blood-brain barrier, resulting in the release of neurotoxins that can ultimately lead to the demise of central nervous system integrity. A high-mesembrine Sceletium tortuosum extract was recently shown to possess cytoprotective and mild anti-inflammatory properties in monocytes and to target specific p450 enzymes to reduce adrenal glucocorticoid synthesis. This is significant since the aetiology of both obesity and diabetes is linked to inflammation and excess glucocorticoid production. Given the interlinked nature of glucocorticoid action and inflammation, central immunomodulatory effects of two Sceletium tortuosum extracts prepared by different extraction methods were investigated. Human astrocytes were pre-treated for 30 min, before exposure to Escherichia coli lipopolysaccharide for 23.5 h (in the presence of treatment). Cytotoxicity, mitotoxicity and cytokine responses (basally and in response to inflammatory stimulus) were assessed. In addition, total polyphenol content, antioxidant capacity and selected neural enzyme inhibition capacity were assessed for both extracts. The high-mesembrine Sceletium extract exerted cytoprotective and anti-inflammatory effects. In contrast, the high delta7-mesembrenone extract, rich in polyphenols, exhibited potent antioxidant effect, although with relatively higher risk of adverse effects with overdose. We conclude that both Sceletium tortuosum extracts may be employed as either a preventative supplement or complimentary treatment in the context of obesity and diabetes; however, current data also highlights the impact that extraction methods can have on plant product mechanism of action.

Keywords

Diabetes Neuroinflammation Oxidative stress Astrocytes Inflammation Type 3 diabetes 

Abbreviations

ANOVA

Analysis of variance

AChE

Acetylcholinesterase

BBB

Blood-brain barrier

CNS

Central nervous system

DMEM

Dulbecco’s modified eagle’s medium

DPBS

Dulbecco’s phosphate-buffered saline

DPPH

1,1-Diphenyl-2-picrylhydrazyl

FBS

Foetal bovine serum

HBSS

Hank’s balanced salt solution

HPLC

High-performance liquid chromatography

IFN-γ

Interferon-gamma

IL-6

Interleukin-6

LPS

Lipopolysaccharide

MAO-A

Monoamine oxidase A

MCP-1

Monocyte chemotactic protein-1

PBS

Phosphate-buffered saline

PI

Propidium iodide

ROS

Reactive oxygen species

RPM

Revolutions per minute

SEM

Standard error of the mean

T2D

Type 2 diabetes

T3D

Type 3 diabetes

Notes

Acknowledgements

We would like to acknowledge the South African National Research Foundation (NRF) for the funding, and Verve Dynamics for the preparation and kind donation of the extracts used in this study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Allen CL, Bayraktutan U (2009) Antioxidants attenuate hyperglycaemia-mediated brain endothelial cell dysfunction and blood-brain barrier hyperpermeability. Diabetes Obes Metab 11:480–490.  https://doi.org/10.1111/j.1463-1326.2008.00987.x CrossRefPubMedGoogle Scholar
  2. 2.
    Anstey KJ, Cherbuin N, Budge M, Young J (2011) Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev 12:426–437.  https://doi.org/10.1111/j.1467-789X.2010.00825.x CrossRefGoogle Scholar
  3. 3.
    Balkwill FR, Burke F (1989) The cytokine network. Immunol Today 10:299–304.  https://doi.org/10.1016/0167-5699(89)90085-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Belanger M, Magistretti PJ (2009) The role of astroglia in neuroprotection. Dialogues Clin Neurosci 11:281–296.  https://doi.org/10.1038/nrn1722 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bennett AC, Smith C (2018) Immunomodulatory effects of Sceletium tortuosum (Trimesemine™) elucidated in vitro: implications for chronic disease. J Ethnopharmacol 214:134–140.  https://doi.org/10.1016/j.jep.2017.12.020 CrossRefPubMedGoogle Scholar
  6. 6.
    Blanco AM, Valles SL, Pascual M, Guerri C (2005) Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol 175:6893–6899.  https://doi.org/10.4049/jimmunol.175.10.6893 CrossRefPubMedGoogle Scholar
  7. 7.
    Burkitt M (2001) Too much of a good thing? Nat Biotechnol 19:811–812.  https://doi.org/10.1136/vr.f2845 CrossRefPubMedGoogle Scholar
  8. 8.
    Carvalho C, Cardoso S, Correia SC, Santos RX, Santos MS, Baldeiras I, Oliveira CR, Moreira PI (2012) Metabolic alterations induced by sucrose intake and Alzheimer’s disease promote similar brain mitochondrial abnormalities. Diabetes 61:1234–1242.  https://doi.org/10.2337/db11-1186 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cásedas G, Les F, Gómez-Serranillos MP, Smith C, López V (2017) Anthocyanin profile, antioxidant activity and enzyme inhibiting properties of blueberry and cranberry juices: a comparative study. Food Funct 8:4187–4193.  https://doi.org/10.1039/c7fo01205e CrossRefPubMedGoogle Scholar
  10. 10.
    Chen YS, Liou HC, Chan CF (2013) Tyrosinase inhibitory effect and antioxidative activities of fermented and ethanol extracts of Rhodiola rosea and Lonicera japonica. Sci World J 2013:1–5.  https://doi.org/10.1155/2013/612739 CrossRefGoogle Scholar
  11. 11.
    Coetzee DD, López V, Smith C (2016) High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor. J Ethnopharmacol 177:111–116.  https://doi.org/10.1016/j.jep.2015.11.034 CrossRefPubMedGoogle Scholar
  12. 12.
    Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95.  https://doi.org/10.1016/0006-2952(61)90145-9 CrossRefGoogle Scholar
  13. 13.
    Gnatek Y, Zimmerman G, Goll Y, Najami N, Soreq H, Friedman A (2012) Acetylcholinesterase loosens the brain’s cholinergic anti-inflammatory response and promotes epileptogenesis. Front Mol Neurosci 5:1–10.  https://doi.org/10.3389/fnmol.2012.00066 CrossRefGoogle Scholar
  14. 14.
    Harvey AL, Young LC, Viljoen AM, Gericke NP (2011) Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids. J Ethnopharmacol 137:1124–1129.  https://doi.org/10.1016/j.jep.2011.07.035 CrossRefPubMedGoogle Scholar
  15. 15.
    Hassing LB, Dahl AK, Pedersen NL, Johansson B (2010) Overweight in midlife is related to lower cognitive function 30 years later: a prospective study with longitudinal assessments. Dement Geriatr Cogn Disord 29:543–552.  https://doi.org/10.1159/000314874 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kaushal V, Dye R, Pakavathkumar P, Foveau B, Flores J, Hyman B, Ghetti B, Koller BH, LeBlanc AC (2015) Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ 22:1676–1686.  https://doi.org/10.1038/cdd.2015.16 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kim YJ, Uyama H (2005) Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future. Cell Mol Life Sci 62:1707–1723.  https://doi.org/10.1007/s00018-005-5054-y CrossRefPubMedGoogle Scholar
  18. 18.
    Ku SK, Kwak S, Kim Y, Bae JS (2014) Aspalathin and Nothofagin from rooibos (Aspalathus linearis) inhibits high glucose-induced inflammation in vitro and in vivo. Inflammation 38:445–455.  https://doi.org/10.1007/s10753-014-0049-1 CrossRefGoogle Scholar
  19. 19.
    De La Monte SM (2008) Alzheimer’s disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol 2:1101–1113.  https://doi.org/10.1177/193229680800200619 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nepal B, Brown LJ, Anstey KJ (2014) Rising midlife obesity will worsen future prevalence of dementia. PLoS One 9:1–5.  https://doi.org/10.1371/journal.pone.0099305 CrossRefGoogle Scholar
  21. 21.
    Patnala S, Kanfer I (2013) Chemotaxonomic studies of mesembrine-type alkaloids in Sceletium plant species. S Afr J Sci 109:5–9.  https://doi.org/10.1590/sajs.2013/882 CrossRefGoogle Scholar
  22. 22.
    Petersen KS, Smith C (2016) Ageing-associated oxidative stress and inflammation are alleviated by products from grapes. Oxidative Med Cell Longev 2016:1–12.  https://doi.org/10.1155/2016/6236309 CrossRefGoogle Scholar
  23. 23.
    Pugazhenthi S, Qin L, Reddy PH (2017) Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta - Mol Basis Dis 1863:1037–1045.  https://doi.org/10.1016/j.bbadis.2016.04.017 CrossRefPubMedGoogle Scholar
  24. 24.
    Shikanga EA, Viljoen AM, Combrinck S, Marston A, Gericke N (2012) The chemotypic variation of Sceletium tortuosum alkaloids and commercial product formulations. Biochem Syst Ecol 44:364–373.  https://doi.org/10.1016/j.bse.2012.06.025 CrossRefGoogle Scholar
  25. 25.
    Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801.  https://doi.org/10.1172/JCI29069.and CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by α7 nicotinic receptors. J Neurochem 89:337–343.  https://doi.org/10.1046/j.1471-4159.2004.02347.x CrossRefPubMedGoogle Scholar
  27. 27.
    Smith C (2011) The effects of Sceletium tortuosum in an in vivo model of psychological stress. J Ethnopharmacol 133:31–36.  https://doi.org/10.1016/j.jep.2010.08.058 CrossRefPubMedGoogle Scholar
  28. 28.
    Sorbara MT, Girardin SE (2011) Mitochondrial ROS fuel the inflammasome. Cell Res 21:558–560.  https://doi.org/10.1038/cr.2011.20 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Streit WJ, Mrak RE, Griffin WST (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1:1–4.  https://doi.org/10.1186/1742-2094-1-14 CrossRefGoogle Scholar
  30. 30.
    Swart AC, Smith C (2016) Modulation of glucocorticoid, mineralocorticoid and androgen production in H295 cells by Trimesemine, a mesembrine-rich Sceletium extract. J Ethnopharmacol 177:35–45.  https://doi.org/10.1016/j.jep.2015.11.033 CrossRefPubMedGoogle Scholar
  31. 31.
    Szelényi J (2001) Cytokines and the central nervous system. Brain Res Bull 54:329–338.  https://doi.org/10.1016/S0361-9230(01)00428-2 CrossRefPubMedGoogle Scholar
  32. 32.
    Thomson CA, McColl A, Cavanagh J, Graham GJ (2014) Peripheral inflammation is associated with remote global gene expression changes in the brain. J Neuroinflammation 11:73.  https://doi.org/10.1186/1742-2094-11-73 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. Journals Gerontol A Biol Sci Med Sci 2014 69:1339–1352. doi:  https://doi.org/10.1093/gerona/glu080 CrossRefGoogle Scholar
  34. 34.
    Wild S, Roglic G, Green A, Sicree R, Hilary K (2004) Global prevalence of diabetes: estimates for the year 2000 and projection for 2030. Diabetes Care 27:1047–1053.  https://doi.org/10.2337/diacare.27.5.1047 CrossRefPubMedGoogle Scholar
  35. 35.
    Wrona D (2006) Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J Neuroimmunol 172:38–58.  https://doi.org/10.1016/j.jneuroim.2005.10.017 CrossRefPubMedGoogle Scholar

Copyright information

© University of Navarra 2018

Authors and Affiliations

  1. 1.Department of Physiological Sciences, Science FacultyStellenbosch UniversityStellenboschSouth Africa
  2. 2.Department of Pharmacy, Faculty of Health SciencesSan Jorge UniversityVillanueva de GállegoSpain

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