**8. Conclusion**

*Parasitology and Microbiology Research*

and IVCAM-1 [5, 143].

(ii) inflammatory cellular components modulation (macrophages, lymphocytes neutrophils); (iii) modulation of expression and/or activity of pro-inflammatory enzymes such as phospholipase A2 (PLA2), cyclooxygenase (COX), lipooxygenase (LOX), iNOS and (iv) modulation of pro-inflammatory gene expression [138]. In malaria inflammation, the immune system-triggering-malaria-toxin is GPI which may be released pRBC rupture at erythrocytic schizogony [70]. GPI initiates TNF-α and lymphotoxin (formerly TNF-β) production [142], up-regulates ICAM-1

Hemopoietic mediators of inflammation comprise Th1/M1 cytokines largely TNF-α, IL-1, IL-6, IL-18 and Th2/M2 cytokines IL-4 and IL-10. When produced excessively as in severe malaria, Th1 cytokines may lead to the generation of fever, hypoglycemia, bone marrow suppression, coagulopathies, hypergammaglobulinemia, hypotension and elevated acute phase reactants [55, 144]. The works by Clark and Chaudhri [144], showing that TNF-α-induced dyserythropoiesis and erythrophagocytosis in malaria-infected animals, evidenced the association of SMA to inflammatory mediators and corroborated

In malaria, hematological differential counts display exaggerated leukocytosis. As inflammatory response is similar regardless of cause, AA may modify Th1 over expression in malaria by eradicating activated cells. Moreover, in a mouse model for pain and inflammation, AA blocked the activation of NF-kβ [147], a major transcription factor in the regulation of pro-inflammatory cells, cytokines and enzymes [148]. In unstimulated Th1 cells, NF-kβ subunit p65/p50, is sequestered in the cytoplasm bound to the inhibitory factor Ikβ-α. Proinflammatory signals in malaria comprising of GPI, cause the phosphorylation of Ikβ-α by Ikβ kinase (IKK) and its inactivation though the ubiquitin-mediated destruction. Liberated, NF-kβ translocate into the nucleus acting as pro-inflammatory mediator and transcription factor [70, 78, 148]. Eradication inflammatory responses is critical for overall health maintenance. AA may be able to inhibit GPI production or maintain inactivation of NF-kβ or both as this anti-inflammatory mechanism has been revealed in other diseases, and not malaria, when similar triterpenoid to AA, madecassoside (MA), was used [149–151]. By inhibiting activation of NF-kβ, AA may subsequently inhibit iNOS and COX-2 and reduce NO release. Moreover, AA (10 mg/kg) injected into Carrageenan-

induced paw edema inhibited expression of iNOS, COX-2 and NF-kβ in mice [147]. This may mean, in malaria, reduction in unrestrained vasodilation related to vascular permeability, pulmonary edema or renal dysfunction. Toxic oxidative activities causing tissue injury may likewise be ablated by a NO reduction and pos-

arginine, exhibited as free energy binding (FEB) of −9.79 kcal.mol<sup>−</sup><sup>1</sup>

model AutoDock v.3.05 to bind iNOS. This binding inhibits iNOS's strong affinity for

Chemoattractant mediators hinging on NF-kβ activation may also be inhibited by AA resulting in abrogation of neutrophil-aggregation and inactivation of the linked oxidant and pro-inflammatory injury lytic enzymes [155]. Activation inhibition of peroxisome proliferator-activated gamma (PPAR-γ), which regulates inflammation through NF-kβ translocation, may be a route AA may confer antiinflammatory activity. A similar process has been confirmed with curcumin, a multi-faceted phytopharmaceutical [156]. The consequent action of this activation

•<sup>−</sup>] [151]. Certainly, AA has been predicted by a computational

[152–154].

Peetre et al. who verified growth inhibition of culture hemopoietic cells [145]. Compounded, the anti-inflammatory outcome of AA may modify proinflammatory apparatuses in malaria in the same way it does in other inflammatory diseases. Indeed, AA displays a dose-dependent (10 and 20 μsg/kg AA) selective induction of selective mitochondria-dependent apoptosis in activated Th1 cells. This averted concanavalin (Con-A)-induced murine fulminant hepatitis in a fashion that disrupted mitochondrial transmembrane potential, released cytochrome c, activated caspases and cleaved poly(ADP-ribose) polymerase [PARP] [146].

**62**

sibly superoxide [O2

The strong connection between malaria pathophysiology and systemic inflammation mobilizes various mediators, metabolic processes consummating in toxic cachexia, hypoglycemia, neuronal damage, coma and death. Numerous immunological and inflammatory response mediators drive the disease. Initial inflammatory response directed at alleviating and curtailing the infection through parasite killing turns around and aberrantly militates against the host. Hormonal involvement is crucial in maintain malaria tolerance by the host. The phytotherapeutics AA, Ma and OA intervention in malaria promises to engage the parasitic as well the inflammation salvaging glucose homeostasis, neuronal death and other disease effects in malaria terminating the vicious cycle and alleviating the disease. Potential alternative treatment regimens for malaria are thus in the offing.
