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Updated: May 20, 2025
Phenotypic Analysis of Rodent Malaria Parasite Asexual and Sexual Blood Stages and Mosquito Stages
Published on: May 30, 2019
Evaluating the effect of new antimalarial N-89 for gametocytes in P. berghei-infected mice
Thi Quyen Dinh1, Hiroaki Matsumori1, Mamoru Niikura2
1Division of International Infectious Diseases Control, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Insights
A new transdermal antimalarial, td N-89, shows promise for children, primarily targeting malaria trophozoites. While not affecting gametocytes, td N-89 demonstrated a 33.3% cure rate in mice, unlike td artemisinin which led to recrudescence.
Area of Science:
- Pharmacology
- Infectious Diseases
- Drug Development
Background:
- Malaria remains a significant threat, particularly to children under five, due to challenges in oral medication administration.
- Existing treatments like Primaquine (PQ) target liver stages and gametocytes but require caution to prevent resistance.
- There is a need for novel antimalarial agents with improved delivery methods and efficacy.
Purpose of the Study:
- To evaluate the efficacy and mechanism of a novel transdermal formulation, td N-89, as an antimalarial agent.
- To investigate the effect of td N-89 on Plasmodium berghei gametocytes and compare its activity to transdermal artemisinin.
- To assess the potential of td N-89 for pediatric malaria treatment.
Main Methods:
- Development of a transdermal formulation (td N-89) for antimalarial drug delivery.
- In vivo testing of td N-89 against Plasmodium berghei in a mouse model.
- Assessment of gametocytocidal activity by measuring gametocyte-related gene expression (Pbs21 and GCS).
- Comparison of td N-89 efficacy and survival rates against transdermal artemisinin.
Main Results:
- Td N-89 demonstrated antimalarial activity, primarily targeting trophozoites.
- Expression of gametocyte markers Pbs21 and GCS increased with td N-89 treatment, suggesting an indirect effect or altered parasite lifecycle.
- Transdermal artemisinin showed higher anti-asexual activity but resulted in 100% mortality due to recrudescence, whereas td N-89 achieved a 33.3% cure rate.
Conclusions:
- Td N-89 is a promising antimalarial candidate, particularly for pediatric use, with a primary target on trophozoites.
- The study provides novel insights into the long-term changes in gametocyte-related gene expression following td N-89 treatment.
- Td N-89 offers a potential alternative to artemisinin-based therapies, showing better survival outcomes in the tested model.
Abstract:
We have developed a transdermal formulation of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (td N-89) for children under the age of five, who account for the majority of malaria deaths, as multiple oral doses are difficult to administer to pediatric. Td N-89 shows promise as a new antimalarial candidate for targeting trophozoites using Plasmodium berghei in vivo. Primaquine (PQ) is currently the only drug that targets the liver stage parasites against P. vivax and P. ovale. When PQ is used in combination to target gametocytes, caution is required to prevent PQ resistance. To investigate the effect of td N-89 on gametocytes, we assess the gametocytocidal activity by measuring the expression levels of gametocyte-related genes following td N-89 treatment. The P. berghei ookinete surface protein (Pbs21) and generative cell-specific 1(GCS) were used as markers for female and male gametocytes. Expression levels of Pbs21 and GCS increased during td N-89 at ED90 dose. In mice with td artemisinin as a reference, Pbs21 and GCS expression levels were higher than those in the td N-89 group, suggesting that td artemisinin exhibited higher anti-asexual parasite activity compared to td N-89. However, all mice treated with td artemisinin showed recrudescence and died. In contrast, 33.3 % of mice treated with td N-89 achieved a cure despite 1.7 % parasitemia. We report for the first time that gametocyte-related genes expression progressively changes in the td N-89 group and can be detected for a long period. Taken together, our results suggest that target of td N-89 is mainly trophozoites and not gametocytes.
