Investigation of the potential beneficial effects of cannabidiol on oro-bucco-lingual dyskinesias, oxidative stress and psychosis using animal studies
Date
2022-12
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Stellenbosch : Stellenbosch University
Abstract
ENGLISH SUMMARY: Background: Oxidative stress is involved in the pathophysiology of schizophrenia and side effects of conventional and atypical antipsychotics such as tardive dyskinesia (TD), weight gain, hyperglycaemia, and hyperlipidaemia. Cannabidiol (CBD) is a potent anti-oxidative and anti-inflammatory agent that also protects against glutamate neurotoxicity. This study’s main objective was to determine if treatment with CBD would attenuate these medications-induced side effects and symptoms of psychosis using a rat model of TD and psychosis.
Methods: A total of 206 rats (n=7-10) was used in this study which was conducted in five stages comprising 26 groups. In the first sets of experiments (subchronic haloperidol 5 mg/kg/oral groups of experiments), six experimental groups were given different combinations of oral cannabidiol with 5 mg/kg/oral of haloperidol. In the second and third sets of experiments (subchronic haloperidol 5 mg/kg/i.p. and chronic haloperidol 50mg/kg/i.m. groups of experiments), haloperidol was administered either sub-chronically via the intraperitoneal (IP) route or chronically via the intramuscular (IM) route to six experimental groups, either alone or in combination with CBD. In the fourth sets of experiments (subchronic risperidone 10 mg/kg/oral groups of experiments), six experimental groups were administered oral risperidone (10 mg/kg) either alone or with oral CBD (5 mg/kg) administered before or after risperidone or concomitantly with risperidone. In the fifth sets of experiments (social isolation experiments), Wistar rats were randomly allocated to either socially isolated groups or socially reared groups with or without pharmacological interventions. Weight and fasting blood sugar (FBS) were measured for all groups. Vacuous chewing movement (VCM), anxiety-like behaviour, locomotor activity, cognition, and coordination were assessed at different time points after the last dose of medication in stages one to four of the study. At the end of the isolation period in the social isolation groups of experiments, the Sociability apparatus (3-chambered social test) was used to assess sociability, locomotion, and social novelty preference. Blood for the oxidative stress assay was collected before the animals were sacrificed. The brain, liver, and kidney were harvested after the animals were sacrificed and derived homogenates were used for oxidative stress parameter assays.
Results: In the subchronic haloperidol 5 mg/kg/oral groups of experiments, CBD co-administration with haloperidol attenuated VCM and poor motor coordination produced by haloperidol. CBD also ameliorated haloperidol-induced increased blood glucose levels. CBD only at 5 mg/kg appeared to have anxiolytic properties, but may not be as effective as haloperidol, which exhibited a greater anxiolytic effect at 5 mg/kg. Treatment with CBD only at 5 mg/kg also appeared to enhance brain 1,1-Diphenyl-2-Picrylhydrazyl (DPPH) scavenging activity. In the subchronic haloperidol 5 mg/kg/i.p. and chronic haloperidol 50 mg/kg/i.m. groups of experiments, oral CBD (5 mg/kg) attenuated the VCM produced by sub-chronic (IP) haloperidol (5 mg/kg) but had minimal effects on the VCM produced by chronic (IM) administration of haloperidol (50 mg/kg). In both sub-chronic (IP) and chronic (IM) haloperidol groups, there were significant changes in brain, liver and kidney oxidative stress parameters compared with the CBD and control groups. In the subchronic risperidone 10 mg/kg/oral groups of experiments oral CBD (5 mg/kg) significantly reduced risperidone-induced elevated FBS. Oral CBD also attenuated risperidone-induced poor motor coordination but did not have significant effects on VCM, cognition and locomotion. Both CBD and risperidone increased the activity of antioxidant enzymes and decreased the activity of pro-oxidant enzymes. In the social isolation experiments, social isolation affected the locomotor activity of the animals suggesting social isolation induced anxiety. However, CBD did not relieve the social isolation-induced anxiety. Social isolation also increased nitric oxide (NO) activity, reduced glutathione (GSH) levels and reduced CAT activity in the brain, all of which were ameliorated by CBD. Social isolation was associated with a reduction in NO production in the kidney which was reversed by CBD.
Conclusion: CBD ameliorated motor impairments produced by haloperidol. Data from this study suggests that CBD can be combined with haloperidol to prevent the emergence of extrapyramidal side effects such as TD. The duration of haloperidol administration also affected the effects of CBD on VCM, and oxidative stress induced by haloperidol. CBD also stabilised FBS and improved motor incoordination induced by haloperidol and risperidone. Both CBD and risperidone exhibited antioxidant properties in the brain. CBD did not improve social cognition or social anxiety but ameliorated social isolation-induced oxidative stress.
AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar.
AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar.
Description
Thesis (PhD)--Stellenbosch University, 2022.