Browsing by Author "Bennett, Amber Clare"

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    Neuro- and immunomodulatory effects of Sceletium tortuosum
    (Stellenbosch : Stellenbosch University, 2018-03) Bennett, Amber Clare; Smith, Carine; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Chronic lifestyle stress translates to chronic physiological and psychological conditions. Continual stress-response activation plays a key role in the development of inflammatory diseases, such as diabetes, Alzheimer’s disease, anxiety and depression. It is known that inflammatory cytokines produced in the periphery can cross the blood-brain barrier, resulting in release of neurotoxins that can lead to demise of central nervous system integrity. Pro-inflammatory cytokines are also responsible for undesired modulation of serotonin signalling and receptor expression. Since two of the major systems implicated in the aetiology of neurodegeneration and psychological illness are central inflammation and maladaptations in serotonergic signalling, it is important to investigate potential therapeutic targets in this context. A high-mesembrine Sceletium tortuosum extract (Trimesemine™) was shown to possess cytoprotective and mild anti-inflammatory properties in human monocytes, and inhibitory effects on adrenal glucocorticoid synthesis. Additionally, it was recently confirmed that claimed selective serotonin reuptake inhibition (SSRI) properties of Sceletium tortuosum are, in fact, secondary to its monoamine-releasing agent (MRA) capacity. A high-Δ7-mesembrenone Sceletium extract has also shown promising anti-oxidant capacity and anti-cancer effects. In this thesis, two models were employed to further investigate the therapeutic potential of Sceletium tortuosum in maladaptations to chronic stress. Firstly, the central immunomodulatory effects of two Sceletium tortuosum extracts, high-mesembrine extract, Trimesemine™, and high-Δ7-mesembrenone extract, Delta-7, were investigated. Human astrocytes were pre-treated with each extract for 30 minutes, before exposure to Escherichia coli lipopolysaccharide for 23.5 hours (in the presence of treatment). Cytotoxicity, mitotoxicity and cytokine responses (basally and in response to inflammatory stimulus) were assessed. Total polyphenol content, antioxidant capacity and selected neural enzyme inhibition capacity were also assessed for both extracts. Trimesemine™ exerted cytoprotective (p<0.0001) and anti-inflammatory effects (p<0.05). In contrast, Delta-7 exhibited potent antioxidant effects (p<0.05), although with relatively higher risk of adverse effects with overdose. The second model employed was a platelet model of the central serotonergic system, to investigate the effects of high-mesembrine Sceletium on serotonin system parameters in anxious and non-anxious individuals. Modulators of the serotonergic system – an SSRI (citalopram) and a mild MRA (Trimesemine™) – were used to investigate the platelet model in anxiety. Isolated platelets from anxious and non-anxious subjects were exposed to a known activator (calcium ionophore A23187) and each modulator for 15 minutes. Cytokine secretion and changes in platelet serotonergic system activity were assessed. Serotonin transporter expression was down-regulated in state anxiety in response to citalopram, validating the platelet model in this context. Basal platelet serotonin levels in individuals exhibiting state/trait anxiety were lower than no-anxiety controls (p<0.05), while platelet activation state was increased (p<0.05). Trimesemine™ was again confirmed to have anti-inflammatory effect by its modulation of pro- and anti-inflammatory cytokine secretion. We conclude that both Sceletium tortuosum extracts may be employed as either a preventative supplement or complimentary treatment in the context of chronic immune-mediated disease. This study has also highlighted key differences between anxious and non-anxious individuals, and between anxiety type, in terms of serotonergic system parameters and inflammatory responses, suggesting diagnostic potential for the platelet model.