Browsing by Author "Annandale, Jenna Fay"

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    Schizophrenia: Effect of Fluanxol® treatment on redox status
    (Stellenbosch : Stellenbosch University, 2021-03) Annandale, Jenna Fay; Smith, Carine; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Oxidative stress has been implicated in the pathology of schizophrenia, with impaired antioxidant mechanisms observed in these patients. The modulatory role of oxidative stress on the activity of NMDA receptors on GABA interneurons impacts neurotransmitter signalling, leading to hyperdopaminergic dysfunction (directly associated with the disease symptoms), microglial activation and a pro-inflammatory shift, rendering these patients susceptible to inflammatory comorbidities. It is therefore important to investigate therapeutic drugs prescribed to schizophrenia patients for their effect on redox status. Flupentixol dihydrochloride (Fluanxol®) is prescribed to patients with schizophrenia and has known antipsychotic effects. However, the mechanisms by which this drug exerts those effects are not yet fully elucidated, particularly in terms of its effect on redox status and inflammation. We aimed to investigate the effect of the antipsychotic, Fluanxol®, on redox status in vitro using BE(2)-M17 neuroblastoma cells, to simulate the target site, and CaCo2 gut epithelial carcinoma cells, to simulate the site of absorption, in the presence or absence of an inflammatory challenge (LPS). Cell viability (WST-1) validated the prescribed doses of Fluanxol® in our cellular models. Oxidant production (H2O2 assay kit), oxidative damage (TBARS (MDA) assay) and antioxidant capacity (TEAC) were assessed to probe the drug’s effect on redox status. Further investigation in vivo in zebrafish was used to assess effect of Fluanxol® on redox at whole organism complexity. After confirming non-toxicity of treatment doses in vivo, zebrafish were subjected to induced seizures using the pentylenetetrazole (PTZ) model, to determine therapeutic dose of Fluanxol® treatment in zebrafish. Activity monitoring was performed using a Daniovision activity tracker and Ethovision software. Optimal therapeutic dose of Fluanxol® treatment was assessed in terms of potential effects on redox status in zebrafish larvae at 4 days post-fertilisation (dpf), using the fluorescent ROS marker CM-H2DCFDA and live organism microscopy. No detrimental effects of Fluanxol® were observed in vitro, in terms of redox status. Dosage adjusted for bioavailability, confirmed that Fluanxol® does not display mitochondrial toxicity at the prescribed doses (3 mg/day to 12 mg/day), but mitochondrial toxicity was observed at an overdose concentration equivalent to 30 mg/day (p<0.0001). In the zebrafish model of psychosis, potential GABAergic effects of Fluanxol® was observed (p<0.0001). In addition, a novel finding was an antioxidant effect of Fluanxol®, as illustrated by reduced ROS (fluorescent intensity (p<0.01) and fluorescent area (p<0.05)) in 5 dpf zebrafish larvae. We conclude that Fluanxol® exhibited in vitro mitochondrial toxicity only at a dose equivalent to human overdose concentration, but that little to no toxicity is present within the prescribed doses. In line with this in vitro data, doses of Fluanxol® showing maximal antipsychotic effect in a zebrafish larval model, also reduced ROS levels, suggesting its therapeutic effect to include a positive outcome in terms of redox status. Finally, the observed antipsychotic effect of Fluanxol® in the PTZ model in zebrafish additionally suggest GABAergic modulation as a potential additional mechanism of action of this drug.