Therapeutic Effects of Isopropyltoluene (p-Cymene) Alone and in Combination with Quinine Against Malaria Infection Through Modulation of Inflammation and Oxidative Stress.

Background: This study aims to evaluate the therapeutic effects and potential mechanisms of p-cymene (CM) alone and in combination with quinine (Qu) against Plasmodium berghei-infected mice. Methods: A total of 108 BALB/c mice were randomly divided into nine groups included six infected groups, which received normal saline, Qu (10 mg/kg), CM 5 mg/kg, CM 10 mg/kg, CM (5 mg/kg) + Qu (10 mg/kg), and CM (10 mg/kg) + Qu (10 mg/kg) as well as three noninfected groups, which received normal saline, CM 5 mg/kg, and CM 10 mg/kg. Mice were intraperitoneally infected by 1 × 106 P. berghei malaria-infected erythrocytes. Infected mice were orally treated daily over a period of 4 days. Then parasite growth suppression (PGS), survival rate, the level of oxidant and antioxidant markers, and analysis of immune response-related genes were also evaluated. Results: The highest survival rate of 100% was observed in infected mice treated with a combination of CM and Qu, which also demonstrated a PGR value of 100% (p < 0.001). The combination of CM and Qu resulted in the most significant reductions in tissue concentrations of malondialdehyde and nitric oxide, while upregulating the expression of the superoxide dismutase, glutathione peroxidase, and interleukin-(IL)10 (>fourfold change) genes resulted in a reduction in the expression level of the tumor necrosis factor (<1.3-fold-change) and IL-1β (<1.4-fold change) genes. The combination of CM and Qu also caused significant modulation of serum levels of liver and kidney markers in malaria-infected mice. Conclusion: The results of this survey indicate that the combination therapy of CM with Qu demonstrates significant effectiveness in treating malaria-infected mice by regulating oxidative stress, enhancing antioxidant enzyme activity, and modulating inflammatory responses. However, to further validate the therapeutic potential of this compound, it is essential to conduct clinical trials that evaluate both its toxicity and therapeutic efficacy.