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Research: Buthionine sulfoximine increases the efficacy of arteether antimalarial activity in arteether-resistant Plasmodium vinckei by glutathione depletion

April 30, 2015 - 07:57 -- Bart G.J. Knols
Ramesh Chandra, Santosh Kumar, Sunil Kumar Puri
MWJ 2015, 6, 4
Article type: 
We tested in vivo effects of L-buthionine (S,R)-sulfoximine (BSO) on glutathione (GSH) and hemozoin formation in arteether-sensitive and - resistant strains of Plasmodium vinckei. Groups of 7-8 Swiss mice were inoculated by intraperitoneal injection (i.p.) with 1×106 parasitized erythrocytes of PvAS (sensitive) or PvAR (resistant) strain of P. vinckei. The infected mice were treated with BSO (Sigma) 400 mg/kg twice a day for four days and blood was collected after the last injection with BSO. A relatively stronger inhibition of GSH level was observed in the blood of mice infected with resistant parasites (62.64%; p<0.0001), whereas inhibition in sensitive strain-infected mice and uninfected mice was 32% (p=0.034) and 35% (p=0.034), respectively. The results also show an inverse relationship between GSH and hemozoin in the arteether-sensitive and -resistant strains. The hemozoin contents in the resistant strain are 0.27±0.09, 0.69±0.14 and 5.30±0.79 μmol/109 cells at 5, 10 and 20% parasitemia, respectively, whereas hemozoin contents in the sensitive strain at the same parasitemia levels are 0.59±0.29, 12.38±1.96 and 30.80±2.27 μmol/109 cells. Moreover, hemozoin formation increased by 80% through the administration of BSO in the arteether-resistant strain, whereas insignificant changes occurred in the sensitive strain. BSO was also found to increase the efficacy of arteether antimalarial activity against the resistant strain in vivo. It is concluded that treatment with BSO significantly reduces the level of GSH, which leads to insufficient growth of resistant parasites. These results suggest that BSO might be helpful in prolonging the persistence of the drug, and pose a promising lead to help reducing the chance of resistance development against artemisinin and its derivatives.



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