Although death in malaria is attributed to cerebrovascular blockage and anaemia, overwhelming cytokine production can contribute to the severity of the disease. Therefore, mitigation of dysregulated inflammatory signalling may provide further benefit for malaria treatment. Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is known to inhibit glycogen synthase kinase-3β (GSK3β), a potent regulator of both pro- and anti-inflammatory effects. Quercetin is therefore a potential therapeutic to modulate the imbalanced cytokine production during malarial infection. Anti-malarial effects of quercetin were evaluated in murine models of severe and cerebral malaria using Plasmodium berghei NK65 and ANKA strains, respectively. Western blotting and analysis of cytokines were carried out to determine the GSK3β-mediated cytokine-modulating effects of quercetin in infected animals. Quercetin (25 mg/kg BW) treatment in P. berghei NK65-infected animals resulted in 60.7 ± 2.4% suppression of parasitaemia and significantly decreased serum levels of TNF-α and IFN-γ, whilst levels of IL-10 and IL-4 were elevated significantly. Western analysis revealed that pGSK3β (Ser9) increased 2.7-fold in the liver of quercetin-treated NK65-infected animals. Treatment of P. berghei ANKA-infected mice with quercetin (15 mg/kg BW) increased (2.3-fold) pGSK3β (Ser9) in the brains of infected animals. Quercetin is a potential plant-derived therapeutic for malaria on the basis that it can elicit anti-malarial and GSK3β-mediated cytokine-modulating effects.

Medicinal plant extracts and bioactive compounds have been extensively studied for their potential anti-malarial activity. These extracts and compounds may combat malaria by directly targeting Plasmodium parasites, modulating the host immune response, or through both mechanisms. However, comprehensive knowledge and documentation of the cell signalling pathways underlying these effects remain limited. Therefore, this review critically examines the medicinal plant extracts and their bioactive compounds with reported anti-malarial properties, focusing on their mechanisms of action in mitigating malaria infection. Studies published between 2000 and 2024 were reviewed to identify the effects on cellular and molecular mechanisms of these extracts and compounds in malaria-infected models. Findings indicate that inhibition of specific proteins within Plasmodium parasites can delay parasite growth and prevent rupture of infected red blood cell membranes. Structural analysis of bioactive compounds revealed that many belong to the terpene class, sharing common functional groups and mechanisms of action. Furthermore, the review highlights the importance function of the nuclear factor kappa B (NF-κB) signalling pathway in regulating cytokine responses. Modulation of NF-κB, either through stimulation or inhibition, can influence the production levels of pro- and anti-inflammatory cytokines, contributing to parasite clearance and mitigation of cytokine storms in the host. This review compiles and compares various models of cell signalling pathways involved in the action of plant-based medicines against malaria, offering valuable insights for future molecular docking studies and drug discovery efforts targeting malaria.

Caffeine is a stimulant that increase alertness in the body. However, little is known on the toxicity effects of caffeine in ICR mice. This study aimed to identify the toxicity effects of caffeine in ICR mice for further anti-malarial investigation. Adult ICR mice were injected with caffeine (5, 10, 20 mg/kg) for four days via intraperitoneal injection (i.p.) and were monitored for 30 days. All doses exhibited no changes in body temperature, locomotor activity and urine colour when compared to control mice. Besides that, there were no signs of piloerection and lethargic whereas the mice body weight kept increasing in 30 days of monitoring. Therefore, the treatment of caffeine with 5, 10 and 20 mg/kg b.w. in ICR mice exhibited no toxicity signs and can be used for further anti-malarial study.