Reproductive and Developmental Toxicity of the Aqueous Root Extract of the Antimalarial Herbal Cryptolepis Sanguinolenta (Lindl.) Schltr (Periplocaceae) in Experimental Animals.

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Cryptolepis sanguinolenta, the West African antimalarial plant, is a known cytotoxic to mammalian cells in vitro, a DNA intercalator and topoisomerase II inhibitor. Malaria is endemic in Africa. The high cost of conventional antimalarial agents would suggest that pregnant women particularly in rural West Africa could be exposed to cryptolepis. Recently, cryptolepis containing products have appeared in Ghanaian pharmacies and herbal shops as male sexual enhancers. Paternal exposure to xenobiotics has an equal chance of having an adverse effect on the health of the conceptus as that of the mother. Using animal models, the effects of cryptolepis on reproduction, foetal development and in vivo mutagenesis is extensively studied in this project. Cryptolepis extract (62.5- 1000 mg/kg) reduced female fertility from 100 % in the control group to 0 % at the highest dose of 1000 mg/kg when given during mating and gestation. However, in females unlike males, pretreatment before mating did not have adverse outcomes on reproduction. Further studies showed that inhibition of ovulation is one the mechanisms of cryptolepis reproductive toxicity. In developmental studies, cryptolepis did not induce malformations (monstrosity) or structural abnormalities. However, early treatment of pregnant mice with cryptolepis resulted in terminations of pregnancy which was as high as 66 % when cryptolepis (100 mg/kg) was introduced on the day of mating till the end of gestation. Intrauterine growth inhibition was significant (p < 0.01) for cryptolepis treatment at 100 - 500 mg/kg. The developmental toxicity observed was largely influenced by the time of treatment with cryptolepis and the developmental stage of the conceptus. In functional toxicity studies, prenatal treatment with cryptolepis delayed the development of sensori-motor systems, caused hyperactivity, anxiety, reduced same sex pair interactions and affected object recognition in first generation animals. It however had minimal effect on spatial and reference memory. In the mounting behavioural test to study the aphrodisiac potential of cryptolepis in mice, acute dosing had insignificant effect on all mounting parameters except penile licking which was very significant (p < 0.001) at all doses tested. All aphrodisiac properties were reversed below control vi values with subacute treatments. Histological studies showed that it affected the histoarchitecture of the testes. Cryptolepis also reduced serum testosterone in male mice significantly at all doses of treatment thus consistent with the lack of aphrodisiac property observed with subacute treatments. Cryptolepis exhibited potent anti-androgenic effects by the chick comb method. It was approximately 31.05 times less potent than the cyproterone acetate used as the standard drug. Furthermore it inhibited exogenous testosterone induced comb growth in the white leghorn chick, Gallus domesticus. Cryptolepis (100 – 1000 mg/kg p.o) also induced significant renal damage. In the dominant male lethal assay for genotoxicity and mutagenicity, cryptolepis (62.5-1000 mg/kg) did not induce significant increase in post implantation losses. Overall, the study shows that the aqueous extract of Cryptolepis sanguinolenta (Periplocaceae) affects reproduction and foetal development in experimental animals. Though results from this study cannot be directly extrapolated to man, caution should be exercised in the use of aqueous extract of Cryptolepis sanguinolenta in pregnancy for the treatment of malaria.
A thesis submitted in fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences