THE EFFECTS OF THE NATURAL PRODUCT PARTHENIN ON THE DEVELOPMENT OF PLASMODIUM IN THE ANOPHELINE MOSQUITO

Parthenin;Plasmodium;Anopheles;not listed

Balaich, Jared NicholasDinglasan, Rhoel R. ;

Johns Hopkins University

关键词: Parthenin;    Plasmodium;    Anopheles;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39249/BALAICH-THESIS-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

AbstractBackground:Parthenin is a natural product with a wide array of biological effects that is derived from the invasive and damaging weed, Parthenium hysterophorus. Parthenin is closely related in structure to artemisinin, which is one of the most important antimalarial drugs in the world today. Both compounds are sesquiterpene lactones and research shows that parthenin also has an effect on Plasmodium blood stage development. This study did not evaluate parthenin as a potential therapeutic against blood stages but rather examined the effect of the compound on the transmissible stages of the parasite within the mosquito to gain potential mechanistic insight. This research could help identify a possible mode of action of parthenin, which may be different from artemisinin; and therefore pave the way for the development compounds more suitable as drugs that would be effective against artemisinin-resistant parasites.Methods:We analyzed the developmental stages of Plasmodium in reverse order in the mosquito. First, serial dilutions of parthenin were included in Plasmodium falciparum gametocytemic blood and fed to Anopheles gambiae mosquitoes to evaluate the effect of the compound on oocyst infection intensity. Ookinete development in the presence of parthenin was subsequently evaluated by immunofluorescence as well as by imaging flow cytometry using a cultureable strain of Plasmodium berghei. Male microgamete exflagellation following 16 min incubation with parthenin was quantified by manual counting under phase contrast microscopy. Finally, to determine if parthenin can act on quiescent stage V gametocytes, the parasites were exposed to parthenin for 24 hours, and fed to mosquitoes without the compound present in the blood meal.Results:Including parthenin in the blood meal resulted in a dramatic decrease in P. falciparum oocyst numbers and was statistically significant at 100, 50 and 25 µg/mL. Ookinete formation in the midgut was also inhibited in a similar fashion at similar concentrations and imaging flow cytometry also demonstrated the absence of mature, in vitro cultured P. berghei ookinetes. As suspected, microgametocyte exflagellation was significantly inhibited by the compound, which directly impacts the number of ookinete produced. P. falciparum stage V gametocytes were rendered inactive after 24 hours of incubation with parthenin at 1 µg/mL as evident by the complete absence of exflagellation and oocyst formation despite the absence of the compound in the gametocytemic blood meal.Conclusion:Parthenin was shown to have significant effects on all tested developmental stages of the parasite including gametocytes, male gametes and ookinetes. The broad inhibitory properties of parthenin on all the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin.