Mefloquine-curcumin combinations improve host mitochondrial respiration and decrease mitotoxic effects of mefloquine in Plasmodium berghei-infected mice

Abstract

Plasmodium infection is a health challenge. Although, antiplasmodial drugs kill the parasites, information on the effects of infection and drugs on the expression of some genes is limited. Malaria was induced in two different studies using NK65 (chloroquine-susceptible, study 1), and ANKA (chloroquine-resistant, study 2) strains of Plasmodium berghei in 30 male Swiss mice (n = 5) in each study. Mice orally received 10 mL/kg distilled water, (infected control), Mefloquine (MF) (10 mg/kg), MF and Curcumin (CM) (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (un-infected) were used as the control. After treatment, total Ribonucleic acid (RNA) was isolated from liver and erythrocytes while Deoxyribonucleic acid (DNA)-free RNA were converted to cDNA. Polymerase Chain Reaction (PCR) amplification was performed and relative expressions of FIKK12, AQP3, P38 MAPK, NADH oxidoreductase, and cytochrome oxidase expressions were determined. Markers of glycolysis, toxicity and antioxidants were determined using ELISA assays. While the expression of FIKK12 was blunted by MF in the susceptible study, co-treatment with curcumin (25 mg/kg) yielded the same results in the chloroquine-resistant study. Similar results were obtained on AQP3 in both studies. Curcumin decreased P38 MAPK in both studies. Plasmodium infection decreased NADH oxidoreductase and cytochrome oxidase but mefloquine-curcumin restored the expression of these genes. While glycolysis and toxicity were inhibited, antioxidant systems improved in the treated groups. Curcumin is needed for effective therapeutic efficacy and prevention of toxicity. Plasmodium infection and treatment modulate the expressions of some genes in the host. Curcumin combination with mefloquine modulates the expression of some genes in the host.

Keywords: Curcumin; Electron transport protein; Malaria; Mefloquine; Plasmodium berghei.

Graphical abstract

Fig. 1

The effects of mefloquine and curcumin combinations on the translocation of FIKK12, expressions of genes for aquaporin-3 and P38 MAPK in mice infected with resistant (A, B, C) and susceptible (D, E, F) strains of P. berghei, respectively. MF = Mefloquine; MF+25C = Mefloquine combined with 25 mg/kg curcumin, MF+50C = Mefloquine combined with 50 mg/kg curcumin; 25C = 25 mg/kg curcumin only; 50C = 50 mg/kg curcumin only. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001.

Fig. 2

The effect of mefloquine and curcumin combinations on the expressions of genes for mitochondrial complexes I (NADH oxidoreductase) and IV 9cytochrome oxidase in mice infected with resistant (A, B) and susceptible (C, D) strains of P. berghei, respectively. MF = Mefloquine; MF+25C = Mefloquine combined with 25 mg/kg curcumin, MF+50C = Mefloquine combined with 50 mg/kg curcumin; 25C = 25 mg/kg curcumin only; 50C = 50 mg/kg curcumin only. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001.

Fig. 3

The effects of mefloquine and curcumin combinations on host glycolytic enzymes (A–F) and immunoglobulins (G–J) in mice infected with susceptible and resistant P. berghei-infected. MF = Mefloquine; MF+25C = Mefloquine combined with 25 mg/kg curcumin, MF+50C = Mefloquine combined with 50 mg/kg curcumin; 25C = 25 mg/kg curcumin only; 50C = 50 mg/kg curcumin only. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001.

Fig. 4

The effect of mefloquine and curcumin combination on antioxidant systems both in susceptible and resistant studies. MF = Mefloquine; MF+25C = Mefloquine combined with 25 mg/kg curcumin, MF+50C = Mefloquine combined with 50 mg/kg curcumin; 25C = 25 mg/kg curcumin only; 50C = 50 mg/kg curcumin only. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001.

Fig. 5

The effect of mefloquine and curcumin combination on some markers of toxicity. The figures shows alanine aminotraansferase in susceptible (A) and resistant (B); aspartate aminotransferase in susceptible (C) and resistant (D); gamma glutamyl transferase in susceptible (E) and resistant (F) studies. MF = Mefloquine; MF+25C = Mefloquine combined with 25 mg/kg curcumin, MF+50C = Mefloquine combined with 50 mg/kg curcumin; 25C = 25 mg/kg curcumin only; 50C = 50 mg/kg curcumin only. * = P < 0.05; ** = P < 0.01; *** = P < 0.001; **** = P < 0.0001.

Fig. 6

Histology of liver and spleen of P. berghei-infected mice treated with drug combinations of mefloquine and curcumin. A = Normal control; B to G indicates susceptible P. berghei-infected mice treated with mefloquine, mefloquine and 25 mg/kg curcumin, mefloquine and 50 mg/kg curcumin, 25 and 50 mg/kg of curcumin only. H to M indicates resistant P. berghei-infected mice treated with vehicle, mefloquine, mefloquine combined with 25 mg/kg curcumin, mefloquine combined with 50 mg/kg curcumin, 25 and 50 mg/kg of curcumin only. The plate labeled N is the spleen from infected mice treated with mefloquine only.