A rodent malarial model of Plasmodium berghei for the development of pyrimethamine and sulphadoxine-pyrimethamine resistant malaria in mice

Abstract

This study investigated the development of pyrimethamine (pyr) and sulphadoxine-pyrimethamine (S/P) resistance in Plasmodium berghei, a rodent parasite in mice using a serial technique (3.50 – 10mg/kg pyrimethamine) and a single treatment course approach with 125/6.25mg/kg S/P. The stability of resistance phenotypes, parasite pathogenic disposition and host leukocyte response were also investigated. The sequential and continuous increased-dose exposure of drug naïve parasites to pyrimethamine resulted in the development of two distinct resistant clone generations: PB10-1 and PB10-2 (3.5mg/kg pyr bypass clone) in 66.7% and 41.7% (P < 0.05) of drugged mice intraperitoneally challenged with 106 parasitized erythrocytes and producing slow ascending parasitaemia (20.4 ± 1.7 vs. 19.1 ± 3.8 %RBC; P > 0.05) on days 13 – 18 post inoculation that was significantly (P < 0.05) lower than the fulminating parasitaemia (27.3 ± 2.1%RBC) occurring on days 3 – 5 post inoculation in undrugged mice. The pyr resistance phenotype in PB10-1 and PB10-2 were observed to exhibit stability of > 10 and 3 – 5 weekly passages respectively in undrugged mice. The two clones further exhibited virulence disparity in their ability to cause significant (P < 0.05) increases in ALT (70.4 – 80.2 ± 3.4 – 3.8 vs. 31.8 ± 1.1 U/L) and AST (78.7 – 84.1 ± 3.1 – 3.7 vs. 38.6 ± 2.4 U/L) and reduction in total peripheral leukocyte count (3.2 – 4. 6 x 103 vs. 1.8 x 104 /mm3) when compared to the control. Resistance to S/P by 10%, 50% and 70% in sensitive, PB10-2 and PB10-1 clones was also observed, suggesting a non-requirement of pyr resistance for the development but necessity for the intensification of S/P resistance.

Keywords: Plasmodium berghei, Malaria, Sulphadoxine-pyrimethamine resistance

Nigerian Journal of Health and Biomedical Sciences Vol. 5 (2) 2006: 30-38