Neuropharmacological effects of the petroleum ether/ethyl acetate stem bark extract of Maerua Angolensis D.C (Capparaceae)

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JUNE, 2016
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The search for novel lead compounds from medicinal plants to ameliorate or cure various disorders is still important and valid. There is a greater and unmet medicinal need when it comes to central nervous system (CNS) disorders. Maerua angolensis is a useful medicinal plant found in most parts of the West-African sub-region including Ghana. It has been employed in the treatment of various CNS disorders including epilepsy and psychosis. The present study examined the anxiolytic, antidepressant and anticonvulsant potential of the petroleum ether/ethyl acetate extract of the stem bark (MAE) in murine and zebrafish models. Preliminary neuropharmacological investigations in the Irwin test showed analgesic effects as well as a general reduction in fear response and motor activity. Further characterization indicated a general CNS depressant effect in the spontaneous locomotor activity and pentobarbitone-induced sleep tests. There was also a trend with respect to protection against death in the seizure liability test although statistical significance was absent when compared to control. Based on the findings of the preliminary study, the anxiolytic potential was assessed in the elevated plus maze (EPM), Suok test (ST) and open field test (OFT) in mice. MAE (30-300 mg kg -1 ), similar to diazepam, showed a significant increase in % open arm entries, a decrease in % protected head-dips and % stretch-attend postures. Oral administration of MAE also reduced anxiolytic parameters in the Suok test without affecting significantly motor coordination. However, MAE treatment revealed significant anxiolytic effects by increasing % centre time, whilst caffeine (anxiogenic agent) reduced % time spent in the central arena. The anxiolytic effects was further evaluated in the novel tank and light-dark zebrafish models. MAE (0.1-1.0 mg mL -1 ) treatment similar to fluoxetine and desipramine showed anxiolytic iv effects in both paradigms. Similar treatment with MAE also proved to be effective in reversing ethanol withdrawal-induced anxiety and anxiety induced by chronic unpredictable stress. The anxiolytic effect in the novel tank and light-dark tests was reversed by pretreatment with granisetron (a 5-HT3 antagonist), cyproheptadine (a 5-HT2A antagonist), methysergide (a 5-HT2B/2C antagonist) and pizotifen (a 5-HT2A/2C and 5-HT1 antagonist). Also concomitant administration of MAE after flumazenil (a GABA A receptor antagonist) treatment suppressed the anxiolytic effect. Taken together, this suggest that the extract possesses true modulation of the serotonergic and GABAergic systems. Acute administration of the extract (100-1000 mg kg -1 , p.o.) exhibited antidepressant effects by reducing the duration of immobility in both the forced swim test (FST) and tail suspension test (TST). Comparing the degree of reduction in immobility after treatment revealed that the efficacy of MAE was higher than that of fluoxetine but lower than after imipramine treatment in both tests. Significant increase in climbing and curling duration in the FST and TST respectively is suggestive of serotonergic and opioidergic interaction of MAE. The anticonvulsant effects of MAE and possible mechanisms involved were further explored in the pentylenetetrazole-induced seizure model in rats. MAE (300 mg kg -1 , p.o.) similar to diazepam significantly delayed the onset as well as decreased the duration and frequency of PTZ-induced seizures. The GABA A receptor antagonist, flumazenil, reversed the anticonvulsant effect of MAE, further suggesting the possible involvement of the GABAergic system in its action. Furthermore, the anticonvulsant effect of MAE (300 mg kg -1 , p.o.) was reversed by pre-treatment with a sub-effective doses of L-arginine or sildenafil indicating a possible interaction with the nitricoxidergic system in the anticonvulsant effects. v In the in vitro antioxidant assay , the extract (0.02-0.2 mg mL -1 ) exhibited significant DPPH scavenging activity (E max=48.46 ± 3.652 %, IC50 =0.1817 mg mL -1 ), superoxide scavenging activity (E max=74.13 ± 8.199 %, IC50 =0.004357 mg mL -1 ) and reduced the degree of lipid peroxidation (E max=50 ± 0.00 %, IC50 =0.8245 mg mL -1 ). However, the in vitro antioxidant properties of MAE was less potent than ascorbic acid, the reference antioxidant, although their efficacies were comparable. Pretreatment with MAE before pentylenetetrazole administration reduced significantly oxidative parameters suggesting the ability to prevent the damaging effects of free radicals in the brain. These findings reveal that the extract has antioxidant properties which may account for some of its neuropharmacological effects. Results from this study suggests that MAE possesses sedative, anxiolytic, anticonvulsant, antidepressant and significant antioxidant effects
A thesis submitted in partial fulfillment of the requirements for the degree of Master of Philosophy in the Department of Pharmacology,