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Doi:10.1016/j.exppara.2007.04.012

Experimental Parasitology 117 (2007) 218–221 Plasmodium berghei: Antiparasitic effects of orally administered Emmanuel A. Ojo-Amaize a,*, Emeka J. Nchekwube a, Howard B. Cottam a, Olusola A. Oyemade a, Akinbo A. Adesomoju b, Joseph I. Okogun a,c a Paraquest, Inc., P.O. Box 998, Bloomington, CA 92316-0998, USA b Department of Chemistry, University of Ibadan, Ibadan, Nigeria c National Institute for Pharmaceutical Research and Development, Abuja, Nigeria Received 8 October 2006; received in revised form 24 April 2007; accepted 25 April 2007 Hypoestoxide (HE) is a diterpene isolated from Hypoestes rosea (Acanthaceae), a plant indigenous to Nigeria. Previous studies dem- onstrated that HE exhibited potent anti-inflammatory and anti-cancer activities in well established animal models but weak in vitro activ-ities in both the anti-inflammation and anti-cancer in vitro screening\ systems. We now report a similar observation in the in vitro andin vivo screening systems for antimalarial activity. The results indicate that while HE exhibits a relatively weak in vitro activity(IC50 = 10 lM versus 0.11 lM for chloroquine) against different strains of cultured P. falciparum parasites, the dose of HE requiredto reduce parasitemia by 90% in Plasmodium berghei-infected mice, is much lower than standard antimalaria drugs (SD90 = 250 lg/kg versus 5 mg/kg for chloroquine). Furthermore, lower doses of HE were much more effective than higher doses in inhibiting parasitedevelopment. The implications of these findings are discussed.
Ó 2007 Elsevier Inc. All rights reserved.
Index Descriptors and Abbreviations: HE, Hypoestoxide; P. berghei, Plasmodium berghei; P. falciparum, Plasmodium falciparum; P. berghei; Hypoestoxide;Mice; Malaria; P. falciparum Malaria remains one of the most important infectious diseases of mankind, killing 1–3 million people and causing morbidity in more than 500 million people annually development for a variety of indications ( Infection with Plasmodium falciparum, the most virulent human malaria parasite is responsible for development of different strains of cultured P. falciparum parasites, cultures were incubated with different concen- The increasing resistance of malaria parasites to trations of HE (from 100· stocks in DMSO) for 48 h, available drugs increases the burden of disease and the beginning at the ring stage. Concentrations yielding need to develop new and effective antimalarial agents ( 50% inhibition were extrapolated from plots of mean percent control activity over inhibitor concentration (). To evaluate the antimalarial effect ofHE in vivo, we utilized a model for treatment of murine This work was supported by Paraquest, Inc.
weeks of age, were purchased from Charles River Corresponding author. Fax: +1 626 914 1575.
E-mail address: (E.A. Ojo-Amaize).
0014-4894/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.exppara.2007.04.012 E.A. Ojo-Amaize et al. / Experimental Parasitology 117 (2007) 218–221 according to institutional regulations in facilities ap- kine production with high doses of HE may be proved by the American Association for Accreditation responsible for its decreased efficacy at increasing doses.
of Laboratory Animal Care. The mice were infected with In support of this notion is the fact that HE has been 1 · 105 Plasmodium berghei-infected erythrocytes (pur- shown to inhibit the production of pro-inflammatory chased from ATCC, Manassas, VA), and treatment with varying doses of HE administered orally once daily for 3 and IL-12 (Ojo-Amaize, unpublished results). The sup- days, was initiated 3 days after infection.
pression of these cytokines has been correlated with exac-erbation of the early phase of blood-stage malaria infection in mice and human Paradoxically, the anti-inflammatory prop- The results indicate that HE exhibits relatively weak erty of HE at higher doses can be useful in protecting inhibitory activities against all strains of P. falciparum against malaria-induced fever which is associated with high levels of TNF-a. Thus, HE clearly induces a biphasic quine-sensitive NF54 strain = 9.5 lM; chloroquine- and response which may just be a case of hormesis, which is the response of a biological entity to an effector, with ben- activity in vitro is most probably due to the fact that cer- eficial results at low doses and detrimental results at high tain metabolites of HE once formed intracellularly may doses depending on the biological context in which it oc- be more active than the parent natural product, HE which needs to be administered in vivo in order to be con- The antimalarial activity of HE was compared with verted to the putative more potent metabolite(s). Unlike other antimalarial drugs at their respective SD90s. The the in vitro results, the in vivo results demonstrate a results demonstrate that the activity of HE was compa- remarkable effect of HE on P. berghei parasite develop- rable to the activities of these drugs and the dose of HE ment ). The maximum inhibitory effect of HE required to inhibit parasite development by 90% was was obtained at a nominal dose of 250 lg/kg. Thus, a much lower than standard antimalarial drugs ( disconnect exists between in vitro and in vivo activities The dried leaf powder of Hypoestes rosea, the parent of HE which might reflect a falciparum/berghei discon- plant of HE was also active in this mouse system and nect. However, this remains to be determined in human supports the herbal use of the plant material for the clinical studies with P. falciparum.
management of malaria by Nigerian natives. A similar Increasing doses of HE resulted in decreased efficacy study (partly sponsored by Paraquest, Inc.) on the (). This phenomenon cannot be explained by tox- icity since the maximally tolerated oral dose in mice was conducted independently in mice, at the National Insti- established in earlier studies to be greater than 750 mg/ tute for Pharmaceutical Research and Development in Abuja, Nigeria. The results were similar to those re- no indications of drug toxicity were observed, such as ported here. HE was shown to possess over 10 times weight loss, hair loss, elevation of liver and cardiac en- the potency of chloroquine in that study (Okogun, zymes, etc. However, inhibition of pro-inflammatory cyto- Table 1Therapeutic effects of varying doses of orally administered Hypoestoxide in P. berghei-infected mice Ten female mice per group were infected i.p. with 1 · 105 P. berghei berghei (EI strain) parasitized RBCs and 3 days later when parasitemia was about0.4%, begun on therapy once daily with either HE or chloroquine, which was continued for 3 days. Parasitemias were evaluated daily on Giemsa-stained smears and the day of death of each mouse that died was recorded. The mean survival time (MST) was calculated from the period betweenparasite infection and the day of death. The % increase in life span (ILS) was calculated using MST for each drug-treated mouse. % ILS = [(MST ofdrug-treated mouse-MST of Vehicle Control)/MST of vehicle control] · 100. The mice that survived were clear of parasites and kept for 6 monthsbefore they were sacrificed. Percent reduction of parasitemia is based on day 6 parasitemia levels after infection and following three treatments withdrug or vehicle.
E.A. Ojo-Amaize et al. / Experimental Parasitology 117 (2007) 218–221 Table 2Comparison of anti-malarial activity of Hypoestoxide with standard anti-malarial drugs in P. berghei-infected mice Ten female mice per group were infected i.p. with 1 · 105 P. berghei berghei (EI strain) parasitized RBCs and 3 days later when parasitemia was about0.4%, begun on therapy once daily for 3 days with indicated doses of drug. Parasitemias were evaluated daily. Percent parasitemia is shown for day 6 afterinfection and following three treatments with drug or vehicle. Percent parasitemia results are expressed as ±standard error of the mean (±SE). SD90 isdefined as the dose that suppresses parasitemia by 90% or more.
of HE conducted in the rat. This unique chemical structure may explain the potent in vivo antimalarial activity of HE.
In an effort to address this possibility, we synthesized theHE-glutathione adduct and tested its antimalarial activityin vivo. When administered orally to P. berghei-infectedmice, the HE-glutathione adduct was not significantly more active than HE. However, this may be due to a lackof bioavailability of the glutathione adduct when adminis-tered exogenously compared to the metabolite formed intracellularly. Nevertheless, HE may be active by loweringGSH levels in the parasite via direct scavenging of GSHand/or by inhibiting the enzymes involved in GSH synthe- Although the mechanism by which HE inhibits malaria sis and recycling. These possibilities will be explored in fu- parasite development is presently unknown, it is worth- while to speculate on a structural feature of HE, the a/b- A more likely mechanism of action of HE however in- unsaturated ketone moiety as shown above. It is possible volves the possible interference with parasite actin assem- that this moiety may interfere with mitochondrial electron bly. The movement of the malaria parasite into a host transport in the parasite as has been shown with b meth- erythrocyte during invasion is thought to involve polymer- Glutathione (GSH) is an endogenous sulfur-containing ical agents such as cytochalasin B can inhibit host cell tripeptide and is a major constituent of cells. GSH serves invasion by the parasite. In earlier studies directed toward several independent functions such as in red blood cells in which GSH levels are normally found in high concen- we demonstrated that HE inhibits endothelial cell migra- trations and serves to reduce methemoglobin back to tion and that this is due to the finding that HE interferes, hemoglobin. The intraerythrocytic malaria parasite uses either directly or indirectly, with actin assembly and cytoki- GSH to detoxify heme, which is produced when the par- nesis. In addition, HE has been shown to inhibit the motil- asite digests hemoglobin in the host cell cytosol. If this ity of sporozoites (Dr. Ana Rodriguez, unpublished heme is not detoxified in the parasite, it accumulates in results). It is possible that the actual target of HE could the membranes and results in permeabilization of the be an actin-associated protein or that HE is acting up- membranes to ions. Indeed, the antimalarial activity of stream from actin assembly so that the dramatic changes chloroquine has been found to be due to its ability to in- in the actin cytoskeleton represent an indirect effect of hibit the degradation of heme by glutathione the drug. Studies to investigate these possible mechanisms Because GSH is used in detoxification reactions to con- In conclusion, we report here for the first time our pre- jugate with chemicals containing certain functional groups liminary data on the antimalarial activity of HE and spec- such as found in halogenated and nitro compounds as well ulate on its possible modes of action.
as allylic compounds and epoxides (), it is ex-pected that HE, which contains one allylic and two epoxidefunctions, would therefore be a very good substrate for cel- lular glutathione conjugation as evidenced by one of itsmetabolites, HE-glutathione adduct (structure shown We thank Drs. Philip J. Rosenthal (UCSF San Fran- above). This metabolite was detected in rat plasma by cisco, CA) and Reto Brun (Swiss Tropical Institute, Swit- LC/MS/MS during preliminary pharmacokinetics studies zerland) for conducting the in vitro experiments, and E.A. Ojo-Amaize et al. / Experimental Parasitology 117 (2007) 218–221 Quinetta Cooper and Taamrat Amaize for technical assis- Murado, M.A., Vazquez, J.A., 2007. The notion of hormesis and the dose- response theory: a unified approach. Journal of Theoretical Biology244 (3), 489–499.
Ojo-Amaize, E.A., Kapahi, P., Kakkanaiah, V.N., Takahashi, T., Shalom-Barak, T., Cottam, H.B., Adesomoju, A.A., Nchekwube,E.J., Oyemade, O.A., Karin, M., Okogun, J.I., 2001. Hypoestoxide, a Adesomoju, A.A., Okogun, J.I., Cava, M.P., Carroll, P.J., 1983. Hypo- novel anti-inflammatory natural diterpene, inhibits the activity of IjB estoxide, a new diterpene from Hypoestes rosea (Acanthaceae).
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Ojo-Amaize, E.A., Nchekwube, E.J., Cottam, H.B., Bai, R., Verdier- Alzeer, J., Chollet, J., Heinze-Krauas, I., Huberchwerlen, C., Matile, H., Pinard, P., Kakkanaiah, V.N., Verna, J.A., Leoni, L., Okogun, J.I., Ridley, R.G., 2000. Phenyl b-Methoxyacrylates: a new antimalarial Adesomoju, A.A., Oyemade, O.A., Hamel, E., 2002. Hypoestoxide, a Pharmacophore. Journal of Medicinal Chemistry 43, 560–565.
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