1.Anti-malarial and cytokine-modulating effects of andrographolide in a murine model of malarial infection
Hassan, W.R.M. ; Basir, R. ; Ali, A.H. ; Embi, N. ; Sidek, H.M
Tropical Biomedicine 2019;36(3):776-791
Malarial pathogenesis involves among others, uncontrolled or excessive cytokine
production arising from dysregulated immune responses mounted by the host to eliminate
the plasmodial parasite. The ubiquitous serine/threonine kinase, glycogen synthase kinase-
3β (GSK3β) is a crucial regulator of the balance between pro- and anti-inflammatory
cytokine productions in the inflammatory response to pathogenic infections.
Andrographolide, a bioactive compound in Andrographis paniculata, displays GSK3-
inhibitory effects. A previous study elsewhere has shown that this compound has antimalarial
activity but the molecular basis of its action is yet to be elucidated. Here we
aimed to study the anti-malarial activity of andrographolide in a murine model of malarial
infection to investigate whether its mechanism of action involves cytokine modulation
and inhibition of GSK3β. Andrographolide showed strong and selective anti-plasmodial
activity (IC50 = 13.70±0.71 μM; SI = 30.43) when tested against cultures of P. falciparum
3D7. Intraperitoneal administration of andrographolide (5 mg/kg body weight (bw)) into P.
berghei NK65-infected ICR mice resulted in chemo-suppression of 60.17±2.12%, and
significantly (P<0.05) improved median survival time of infected mice compared to nontreated
control. In addition, andrographolide treatment significantly (P<0.05) decreased
the level of serum pro-inflammatory cytokine, IFN-γ (1.4-fold) whilst the anti-inflammatory
cytokines, IL-10 and IL-4 were increased 2.3- and 2.6-fold respectively. Western blot analyses
revealed that andrographolide treatment of P. berghei NK65-infected mice resulted in an
increased level of phosphorylated GSK3β (Ser9) in liver of infected mice. Andrographolide
administration also decreased the levels of phosphorylated NF-κB p65 (Ser536) and
phosphorylated Akt (Ser473) in liver of malaria- infected animals. Taken together, our
findings demonstrate that the cytokine-modulating effect of andrographolide in
experimental malarial infection involves at least in part inhibition of NF-κB activation as a
consequence of GSK3β inhibition. Based on its cytokine-modulating effects, andrographolide
is thus a plausible candidate for adjunctive therapy in malaria subject to clinical evaluations.
2.Medicinal plants with antimalarial activities mediated via glycogen synthase kinase-3 beta (GSK3β) inhibition
Hassan, W.R.M. ; Ali, A.H. ; Basir, R. ; Embi, N. ; Sidek, H.M.
Tropical Biomedicine 2022;39(No.3):384-393
Many of the therapeutic effects of plant extracts and bioactive compounds appear related to their
immunomodulatory effects and impact on the host immune system. The immune response is desirable
to mitigate established infections and, in the case of severe malaria, is a feasible approach to dealing
with the overwhelming cytokine response. Glycogen synthase kinase-3 (GSK3), a Ser/Thr kinase that
is a central regulator of the cytokine response, is a promising antimalarial drug target. In this review,
we discussed our ongoing research projects, which include assessing the antimalarial activities of
medicinal plants and their bioactive compounds, immunomodulatory activities mediated by GSK3, and
the potential inflammatory pathway involved in malarial infection.