An evaluation of the central and sexual behavioural effects and toxicity of the root extract of Sphenocentrum Jollyanum Pierre (Menispermaceae)

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Roots of Sphenocentrum jollyanum are used as CNS stimulant and aphrodisiac in Ghanaian traditional medicine. The present study is aimed at evaluating the central and sexual behavioural effects and toxicity of the root extract of S. jollyanum Pierre. Extracts of S. jollyanum (SJE) (100, 300 and 1000 mg kg-1 p.o) enhanced mounting and mating behaviour by increasing mounting frequency, intromission frequency and prolonged ejaculation latency. In addition, a decrease in mounting latency, intromission latency and post-ejaculatory interval were observed. These observations indicate increased libido and enhanced sexual behaviour. The dose-response curves of some of the parameters measured (attempted mounts, mounting frequency, anogenital sniffing and penile licking) were U-shaped. Also, the effect of the extract on FSH, LH, prolactin and testosterone levels in rats were determined at weekly intervals for three weeks. Levels of testosterone were increased 4-fold by the third week and there was about 30% increase in FSH levels by the second week which dropped by the third week. Surprisingly, LH levels were reduced by the second week with no significant change in levels of prolactin. These results suggest that there may be more than one mechanism of action of the extract. The immediate increase in sexual behaviour by SJE may be due to a central stimulatory effect whilst long-term effect might be due to increased testosterone levels. To evaluate the effect of the alcoholic root extract of S. jollyanum on smooth muscle, anococcygeus smooth muscle and corpus cavernosum were employed. The cumulative application of the extract relaxed the contraction maintained in the isolated anococcygeus of a rat, induced by high potassium. The extract (0.1-10.0 mg ml-1) also reduced in a concentration-dependent way the maximum response of concentration-response curve to carbachol, phenylephrine and calcium in the anococcygeus muscle. Apart from that, the extract dose-dependently relaxed phenylephrine-precontracted corpus cavernosum smooth muscle. In the tissues investigated, the extract caused a non-specific reduction in both the natural tone and agonist-induced contractions. The extract was found to have constituents (flavonoids and alkaloid corresponding to berberine) which have recorded smooth muscle relaxation via Ca2+ mobilization effect. It is therefore possible that the observed effect of the extract is through membrane stabilization or inhibition of a common pathway in the signal transduction mechanism possibly Ca2+ mobilization. This direct effect exerted on the penile tissue by SJE could also contribute to its copulatory performance-enhancing actions. The effect of the root extract on anxiety was assessed using multiple behavioural paradigms - hole-board, elevated plus-maze (EPM), light/dark box and open field. Adult male mice were treated with SJE (30 - 300 mg kg-1, p.o.), caffeine (10 - 100 mg kg-1i.p.), diazepam (0.1 - 1.0 mg kg-1, i.p) or saline (10 ml kg-1) 30 min before subjected to the behavioural paradigms. Caffeine and the extract decreased percentage open-arm time and entry as well as locomotor activity in EPM indicative of anxiogenicity. The number and duration of head dip also decreased (31.7 - 68.1 % and 60 – 84% respectively) for SJE. Furthermore, there was a dose-dependent increase in the time spent at the corners and decreases in locomotor activity in open field (1 7.3 - 30.65% and 40.25 - 70.39% respectively) as compared to the control. In contrast, diazepam (1.0 mg kg-1, i.p.) exhibited the typical profile of an anxiolytic drug by, increasing the time spent and entries into open arms as well as locomotor activity by 70%, 83.33% and 25.52% respectively. Diazepam also decreased the time spent at the corners and increased locomotor activity in open field. These results indicate that SJE has CNS stimulant activity, which correlates well with the traditional uses of the plant. The effect of SJE on depression was evaluated in the forced swimming test (FST) and the tail suspension test (TST). SJE significantly decreased immobility periods of mice in both the FST and the TST. These indicate that, the extract possesses anti-depressant-like property. The extract did not have a significant effect on motor co-ordination, confirming the assumption that the anti-depressant-like effect is specific. The present study also investigated the contributions of monoamines to the acute behavioural effects of SJE by depleting serotonin (5-HT), or norepinephrine (NE) and dopamine (DA). Catecholamine synthesis was inhibited by α-methyldopa (MeDOPA), whereas reserpine was used for the disruption of vesicular storage of catecholamine. Neither treatment completely prevented responses to SJE, or fluoxetine except that of imipramine in the TST. Depleting both newly synthesized and vesicular components of NE and DA transmission with a combination of reserpine and α-methyldopa (MeDOPA) completely prevented the behavioural effects of SJE and fluoxetine and attenuated those of imipramine. Thus, SJE elicited a significant antidepressant-like effect in mice and may possibly exert it effects by modifying monoamine transport and/or metabolism. In the toxicological study, there were no significant differences found in most of the hematological, serum biochemical parameters and organ/body weight ratio. No abnormality was found in any organ during histopathological examination and no evidence of mutagenicity using Salmonella typhimurium TA97, TA98, TA100 and TA102 tester strains. The extract, however, caused a significant increase in cytochrome P450 which correlated with the decreased pentobarbitone induced sleeping times. The results showed that the no-observed adverse- effect level (NOAEL) of SJE was >1000 mg kg-1 body weight per day in rats, which can be regarded as virtually non-toxic. In conclusion, SJE had no overt organ specific toxicity but demonstrates a potential for drug interactions via induction of cytochrome P450-mediated metabolism in the rat. Collectively, these findings support the use of S. jollyanum in traditional medicine.
A thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Medicine, School of Medical Sciences.