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Published on: December 9, 2014
1NM-PP1 treatment of mice infected with Toxoplasma gondii
Tatsuki Sugi1, Kentaro Kato, Kyousuke Kobayashi
1Department of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Abstract:
Bumped kinase inhibitors (BKIs) target analog-sensitive kinases, which the genomes of mammals rarely encode. Previously, we demonstrated that a BKI effectively suppressed the in vitro replication of Toxoplasma gondii, the causative pathogen of toxoplasmosis, by targeting T. gondii calcium-dependent protein kinase 1 (TgCDPK1) (Eukaryotic Cell, 9: 667-670). Here, we examined whether the BKI 1NM-PP1 reduced parasite replication in vivo. A high dose of 1NM-PP1, by intraperitoneal injection, just before the parasite inoculation effectively reduced the parasite load in the brains, livers, and lungs of T. gondii-infected mice, however, a low dose of 1NM-PP1 with oral administration didn't change the survival rates of infected mice.
Insights
Bumped kinase inhibitors (BKIs) show promise against toxoplasmosis. A high dose of BKI 1NM-PP1 reduced parasite load in mice, but low oral doses did not improve survival rates.
Area of Science:
- Parasitology
- Molecular Biology
- Pharmacology
Background:
- Toxoplasma gondii causes toxoplasmosis.
- Bumped kinase inhibitors (BKIs) target analog-sensitive kinases.
- A BKI previously suppressed in vitro Toxoplasma gondii replication by inhibiting TgCDPK1.
Purpose of the Study:
- To evaluate the in vivo efficacy of the BKI 1NM-PP1 against Toxoplasma gondii.
- To determine if 1NM-PP1 reduces parasite load and improves survival in infected mice.
Main Methods:
- Infection of mice with T. gondii.
- Administration of high-dose 1NM-PP1 via intraperitoneal injection.
- Administration of low-dose 1NM-PP1 via oral gavage.
- Quantification of parasite load in brains, livers, and lungs.
- Monitoring of mouse survival rates.
Main Results:
- High-dose intraperitoneal injection of 1NM-PP1 significantly reduced T. gondii parasite load in mouse brains, livers, and lungs.
- Low-dose oral administration of 1NM-PP1 did not alter survival rates in infected mice.
- The study highlights a dose-dependent and administration-route-dependent effect of 1NM-PP1.
Conclusions:
- The BKI 1NM-PP1 demonstrates in vivo efficacy in reducing T. gondii parasite burden when administered at high doses intraperitoneally.
- Oral administration of low-dose 1NM-PP1 is insufficient to improve survival in a murine model of toxoplasmosis.
- Further research is warranted to optimize BKI delivery and dosage for effective toxoplasmosis treatment.
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