The Antimalarial Effect of Curcumin Is Mediated by the Inhibition of Glycogen Synthase Kinase-3β

Abstract

Curcumin, a bioactive compound in Curcuma longa, exhibits various pharmacological activities, including antimalarial effects. In silico docking simulation studies suggest that curcumin possesses glycogen synthase kinase-3β (GSK3β)-inhibitory properties. The involvement of GSK3 in the antimalarial effects in vivo is yet to be demonstrated. In this study, we aimed to evaluate whether the antimalarial effects of curcumin involve phosphorylation of host GSK3β. Intraperitoneal administration of curcumin into Plasmodium berghei NK65-infected mice resulted in dose-dependent chemosuppression of parasitemia development. At the highest dose tested (30 mg/kg body weight), both therapeutic and prophylactic administrations of curcumin resulted in suppression exceeding 50% and improved median survival time of infected mice compared to control. Western analysis revealed a 5.5-fold (therapeutic group) and 1.8-fold (prophylactic group) increase in phosphorylation of Ser 9 GSK3β and 1.6-fold (therapeutic group) and 1.7-fold (prophylactic group) increase in Ser 473 Akt in liver of curcumin-treated infected animals. Following P. berghei infection, levels of pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-10, and IL-4 were elevated by 7.5-, 35.0-, 33.0-, and 2.2-fold, respectively. Curcumin treatment (therapeutic) caused a significant decrease (by 6.0- and 2.0-fold, respectively) in serum TNF-α and IFN-γ level, while IL-10 and IL-4 were elevated (by 1.4- and 1.8-fold). Findings from the present study demonstrate for the first time that the antimalarial action of curcumin involved inhibition of GSK3β.

GSK3β: A plausible molecular target in the cytokinemodulating effect of exogenous insulin in a murine model of malarial infection

“…To our knowledge, there is currently no evidence about the anti-plasmodial and anti-malarial activities of insulin. The findings from the present study represent the first report that exogenous insulin exhibits anti-malarial activity in a murine model of malarial infection and corroborate previous reports that compounds with GSK3-inhibitory effect (Ali et al, 2017;Hassan et al, 2019) can elicit active (>60%) chemo-suppressive activity and improve animal survivability. On its own, insulin does not exhibit anti-plasmodial activity when tested in vitro (data not shown).…”

“…Additionally GSK3, an important downstream component during insulin signaling is phosphorylated and consequently inhibited (Kaidanovich-Beilin & Woodgett, 2011). Based on studies in our laboratory and elsewhere that LiCl (Zakaria et al, 2010;Ali et al, 2017) and other GSK3 inhibitors (Sudi et al, 2018;Hassan et al, 2019) were able to exhibit anti-malarial activity and modulate the inflammatory cytokine response in murine models of malarial infection, we extend our investigation on GSK3 inhibitors to study the effect of insulin administration on suppression of parasitaemia and cytokine production in mice infected with P. berghei. To our knowledge, there is currently no evidence about the anti-plasmodial and anti-malarial activities of insulin.…”

“…GSK3 was first identified by Embi et al (1980) as an important serine/threonine kinase in the regulation of glycogen metabolism mediated by insulin signalling. Significant findings from our laboratory and elsewhere revealed that LiCl, a GSK3 inhibitor, suppressed parasitaemia development (Zakaria et al, 2010), modulated cytokine production (Ali et al, 2017;Hassan et al, 2019) and improved cognitive function (Dai et al, 2012) in rodent models of malarial infection. Since GSK3 is an established target of lithium (Liu & Yao, 2016), and is pivotal in regulating inflammatory responses during infection, agents that can cause inhibition of GSK3β and modulate cytokine production may be potentially useful as adjunctive therapeutics for malaria.…”

Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites

“…Phytochemicals such as ISO from Inula helenium , trigonoreidon B from Rigonostemon reidioides , betulin from the bark of birch trees, and xanthohumol from Humululus lupulus were able to induce inhibition of the inflammatory response by phospho-inhibition of GSK3β in BV2 and Raw 264.7 cells, and mice lung, respectively, treated with LPS from E. coli O55:B5 or LPS (UO) ( 61 , 62 – 65 ). The phytopigments curcumin and anthocyanins exhibited anti-inflammatory activity in mice infected with the protozoan parasite Plasmodium berghei and also decreased the inflammatory response induced by LPS (UO) stimulation through an increase in phospho-GSK3β-Ser9 ( 66 , 67 ) ( Table S1 ) .…”

Curcumin Provides Hepatoprotection against Amoebic Liver Abscess Induced by Entamoeba histolytica in Hamster: Involvement of Nrf2/HO-1 and NF-κB/IL-1β Signaling Pathways

“…Furthermore, antibacterial, antiviral, and antifungal activity of curcumin has been reported [31]. Likewise, curcumin has been shown to possess antiparasitic activity against malaria and Giardia lamblia [32, 33]. Recently, it was determined by trypan blue exclusion test that curcumin affects the growth and cell viability of E. histolytica , in a time- and dose-dependent manner [34].…”