**6. Inflammation and the pathogenesis of cerebral malaria**

Cerebral malaria is the most severe neurological complication of malaria. It is a clinical syndrome characterized by coma and other acute and or chronic neurological disturbances. In children, coma may develop with seizures often following weakness and prostration. Other neurological symptoms include encephalitis, intracranial hypertension, retinal changes and brainstem signs (impaired pupillary reflexes, posture problems and abnormal eye movements) [116, 117]. In adults, patients develop fever and headaches and progressive delirium and coma but seizures and retinal abnormalities are less common [116, 117]. Several neurological sequelae have been associated with cerebral malaria and these include; spasticity (hemiplegia, quadriparesis or quadriplegia), hypotonia, cranial nerve palsies, ataxia, visual disturbances, aphasias,

*Parasitology and Microbiology Research*

possible oxidative stress.

**homeostasis**

parasite food vacuole membranes destroying it in the process. Chloroquine and other 4-aminoquinolines use this principle to dislocate parasite proliferation by

There is a high overall oxidative load that the host cell immune response to parasitemia likewise yields to the pRBC. Nevertheless, the parasite has developed mechanisms for amplified antioxidant capacity, which may only be overcome by an extremely oxidative agent [83, 90–93]. Agents that inhibit hemozoin creation from heme have since been rendered impotent through multidrug resistance (MDR) processes that extrude the drug from the food vacuole protecting the parasite from

On the other hand, ROS may be deliberately generated and targeted at certain parasite enzymes and membranes, as what is witnessed in the use of endoperoxidase antimalarials, with higher chances of faster parasitemia clearance although

Antioxidants may have an anti-inflammatory effect in malaria where inflammation is generated from OS. However, OS is beneficial in malarial parasite eradication. Pleiotropic characteristics of triterpenes, antioxidant and pro-oxidant, seem to be very ideal properties for combating malaria. Indeed, it has since emerged that certain phytotherapeutics do eradicate parasitemia while ameliorating the pathophysiology of malaria like inflammation [95] and severe malaria anemia [96]. Buttressing the antioxidant capacity of triterpene phytotherapeutics are findings that oral administration of Asiatic acid (20 mg/kg) in streptozotocin-induced diabetic rats up-regulated both enzymatic and non-enzymatic antioxidants with subsequent lipid peroxidation abating [97] and salvaged diabetic rats [98] where increased OS is common. Of note is that superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), ascorbic acid and reduced glutathione (GSH) tend to be elevated in the phytochemical is administered animal experimental DM [97–99]. Moreover, severe malaria is accompanied by marked lipid peroxidation, prevention of which by triterpenes testifies their efficacy against OS

inhibiting heme biocrystallization in pRBC's and increasing OS [85–89].

with higher tissue inflammation induction as well [94].

driven inflammation in malaria and acute renal injury [100].

**5. Hormonal anti-inflammatory processes in malaria mediate glucose** 

Complications of malaria including CM, SMA, placental malaria, hypoglycemia, ARDS are not efficaciously resolved despite the effective parasitemia inhibition by current antimalarial agents [9]. Parasite infection and/or exaggerated immune reaction [101] contribute to malarial complications necessitating treatment emphasis on more than just pathogen clearance but extending it to host defense mechanism that do not interfere with parasitemia load. The malarial disease tolerance or anti-disease process has been linked to heme oxygenase [102] and to Fe3+ sequestration protein ferritin [103] and some novel phytotherapeutics [96]. Glucocorticoids (GC), cortisol in the human and corticosterone in rats and mineral corticoids (MC) are adrenal gland cortex products and the adrenaline-noradrenaline combination are from the adrenal medulla. Adrenal cortex responds to the circadian rhythm, when the hypothalamuspituitary–adrenal axis is activated, in stress/trauma situations, infection or systemic inflammation [104] by producing hormones to influence metabolism, immunity, bone remodeling, cardiovascular function, reproduction and cognitive processes [105]. GC's have anti-inflammatory properties and differential effects on numerous leukocytes phenotypes [106, 107]. In response to GC's, liver, muscle, adipose tissue increase gluconeogenesis, protein catabolism and lipolysis, respectively, to increase glucose directly or indirectly [108]. Upon human malarial (*P. falciparum* or *P. vivax*)

**56**

neurocognitive deficits, epilepsy and some behavioral and neuropsychiatric disturbances. These sequelae may occur in the short-term and resolve, or may persist long term [117].

The pathogenesis of cerebral malaria has been be explained according to two theories: (1) the occlusion theory, or (2) the inflammation theory. The occlusion theory, supported by vast scientific evidence, suggests that brain injury and the resultant neurological disturbances are the result of increased sequestration of blood cells to the brain microvasculature which reduces perfusion and may cause ischemia and tissue injury. Increased sequestration of infected red blood cells, leukocytes and platelets is well known to occur in cerebral malaria [118–120] but the occlusion theory does not adequately explain how some fatal cases of cerebral malaria occur with little to no sequestration. Additionally, although *P. vivax* is not likely to sequester in brain vasculature, there have been isolated cases of *P. vivax* infection-related cerebral malaria cases [121]. These gaps in our knowledge of the pathogenesis of cerebral malaria have led to an increased interest in other possible pathologic mechanisms which may work independently or together with occlusion to cause cerebral malaria and related neurological disturbances. Stimulation of a local inflammatory response in the brain has been coined as an alternative or accompanying mechanism in the pathogenesis of cerebral malaria and is summarized in **Figure 1**.

The blood brain barrier (BBB) endothelium responds to PAMPs, DAMPs and peripheral cytokines and is now regarded as an integral part of the neurovascular unit. In response to these immunostimulatory molecules, endothelial cells produce proinflammatory cytokines and chemokines that mediate leukocyte recruitment and thus trigger local inflammation [122, 123]. Leukocytes further release proinflammatory cytokines and thus set up a vicious inflammatory cycle which exacerbates local inflammation with the brain. As part of the BBB, the integrity of the endothelium is central to BBB function and brain protection. Inflammatory activation of the endothelium has been associated with increased BBB permeability through the induction of regulatory miRNAs that reorganize endothelial tight junctions [124, 125]. This renders the BBB leaky and allows passage of substances into neural tissue, leading to neurotoxicity. Clinically the progression of cerebral malaria has been closely associated with changes in BBB function as evidenced by hemorrhages in cerebral malaria and loss of endothelial intercellular junctions in pediatric fatal cerebral malaria (**Figure 2**) [132].

**59**

**7. Medicinal plants**

*pediatric fatal cerebral malaria [126].*

**Figure 2.**

*Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene…*

The production of proinflammatory cytokines in the brain could also be involved the development of encephalopathy. For example, TNF has been reported to regulate synaptic function and to cause glutamate neurotoxicity [127]; mechanisms which are closely linked to the development of seizures and neurocognitive deficits. IL-1 and TNF have also been shown to inhibit long term potentiation [128] and it is possible that high levels of these cytokines produced in severe malaria could be involved in

*Inflammatory events involved in the pathogenesis of cerebral malaria endothelial intercellular junctions in* 

Exposure to Plasmodium infection leads to elevation of pro-inflammatory markers such as TNF-α and interleukin-1 (IL-1) from macrophages and lymphocytes. Natural products have attracted interest due to their affordability to the general communities with low socio-economic status. Below is the description of the

CDDO-EA (**Figure 3**) is a synthetic oleanolic derivative that has been shown to possess various biochemical activities which include efficacy against cerebral malaria (CM) [129]. The development of severe CM is associated with dysfunction of the

the development of cognitive deficits associated with the disease.

**7.1 Synthetic oleanolic (SO) pentacyclic triterpenes derivatives**

triterpenes that possess anti-inflammatory properties.

*DOI: http://dx.doi.org/10.5772/intechopen.88731*

**Figure 1.** *Malaria Cycle and therapeutic possible cites [18].*

*Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene… DOI: http://dx.doi.org/10.5772/intechopen.88731*

#### **Figure 2.**

*Parasitology and Microbiology Research*

fatal cerebral malaria (**Figure 2**) [132].

*Malaria Cycle and therapeutic possible cites [18].*

term [117].

neurocognitive deficits, epilepsy and some behavioral and neuropsychiatric disturbances. These sequelae may occur in the short-term and resolve, or may persist long

in the pathogenesis of cerebral malaria and is summarized in **Figure 1**.

The blood brain barrier (BBB) endothelium responds to PAMPs, DAMPs and peripheral cytokines and is now regarded as an integral part of the neurovascular unit. In response to these immunostimulatory molecules, endothelial cells produce proinflammatory cytokines and chemokines that mediate leukocyte recruitment and thus trigger local inflammation [122, 123]. Leukocytes further release proinflammatory cytokines and thus set up a vicious inflammatory cycle which exacerbates local inflammation with the brain. As part of the BBB, the integrity of the endothelium is central to BBB function and brain protection. Inflammatory activation of the endothelium has been associated with increased BBB permeability through the induction of regulatory miRNAs that reorganize endothelial tight junctions [124, 125]. This renders the BBB leaky and allows passage of substances into neural tissue, leading to neurotoxicity. Clinically the progression of cerebral malaria has been closely associated with changes in BBB function as evidenced by hemorrhages in cerebral malaria and loss of endothelial intercellular junctions in pediatric

The pathogenesis of cerebral malaria has been be explained according to two theories: (1) the occlusion theory, or (2) the inflammation theory. The occlusion theory, supported by vast scientific evidence, suggests that brain injury and the resultant neurological disturbances are the result of increased sequestration of blood cells to the brain microvasculature which reduces perfusion and may cause ischemia and tissue injury. Increased sequestration of infected red blood cells, leukocytes and platelets is well known to occur in cerebral malaria [118–120] but the occlusion theory does not adequately explain how some fatal cases of cerebral malaria occur with little to no sequestration. Additionally, although *P. vivax* is not likely to sequester in brain vasculature, there have been isolated cases of *P. vivax* infection-related cerebral malaria cases [121]. These gaps in our knowledge of the pathogenesis of cerebral malaria have led to an increased interest in other possible pathologic mechanisms which may work independently or together with occlusion to cause cerebral malaria and related neurological disturbances. Stimulation of a local inflammatory response in the brain has been coined as an alternative or accompanying mechanism

**58**

**Figure 1.**

*Inflammatory events involved in the pathogenesis of cerebral malaria endothelial intercellular junctions in pediatric fatal cerebral malaria [126].*

The production of proinflammatory cytokines in the brain could also be involved the development of encephalopathy. For example, TNF has been reported to regulate synaptic function and to cause glutamate neurotoxicity [127]; mechanisms which are closely linked to the development of seizures and neurocognitive deficits. IL-1 and TNF have also been shown to inhibit long term potentiation [128] and it is possible that high levels of these cytokines produced in severe malaria could be involved in the development of cognitive deficits associated with the disease.

#### **7. Medicinal plants**

Exposure to Plasmodium infection leads to elevation of pro-inflammatory markers such as TNF-α and interleukin-1 (IL-1) from macrophages and lymphocytes. Natural products have attracted interest due to their affordability to the general communities with low socio-economic status. Below is the description of the triterpenes that possess anti-inflammatory properties.

#### **7.1 Synthetic oleanolic (SO) pentacyclic triterpenes derivatives**

CDDO-EA (**Figure 3**) is a synthetic oleanolic derivative that has been shown to possess various biochemical activities which include efficacy against cerebral malaria (CM) [129]. The development of severe CM is associated with dysfunction of the

immune system as shown by plasma levels of TNF-α and IFN-γ [59, 130]. A single injection dose of CCDO-EA (200 μmol/kg) lowered circulating levels of TNF-α and IFN-γ which improved mice survival and lowered inflammation [129]. Indeed, studies have indicated that the host's response to malaria is excess production of pro-inflammatory molecules which are thought to be central causes of inflammation in malaria.

## **7.2 Ursolic acid**

Ursolic acid (3-hydroxy-urs-12-ene-28-oic acid, **Figure 4**) is triterpene which is widely distributed on different medicinal plants. UA has been shown to exhibit a number of pharmacological activities which include, anti-microbial [132], anti-malarial [133] and potent anti-inflammatory properties [134]. Although

**Figure 3.** *Chemical structure of a synthetic oleanolae derivative [129].*

**61**

**Figure 5.**

*Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene…*

no research has been done on anti-inflammatory properties of this triterpene in malaria rats, several studies have evaluated anti-inflammatory properties on other experimental models in vivo and in vitro [134]. However, several studies have evaluated the anti-inflammatory properties of the compounds in in-vitro and in vivo. Tsai and Yin's reports indicate that UA and oleanolic acid (OA) alleviate inflammation through reduction of IL-6 and TNF-α [135]. Additionally, studies also validate the anti-inflammatory potency of UA by reducing the production of IL-2 and through activation of T-helper cells [136]. Liu et al., have shown that UA suppressed T cell responses including NF-kB inhibition at 25 mM while Bharata et al. demonstrated the efficacy against a lowers dose of UA IS enough to lower immune cells such as T-cells, B-cell, and macrophage activation. Apart from this, Xu et al. have shown that anti-inflammatory effects of UA are mediated through.

Maslinic acid and oleanolic acid are two triterpenes widely abundant in olive trees and *Syzygium* spp. Among many pharmacological properties, these triterpenes have demonstrated efficacy against malaria [133]. The triterpenoids are generally highly hydrophobic, which reduces their bioavailability and efficacy. Sibiya et al. showed that once off application of an-OA patch reduces parasitemia and TNF-α plasma levels [137]. Exposure of the host to malaria activates macrophages which in turn induces production of TNF-α and then the release of other cytokines such as IL-6 which initiate inflammation. Reports also indicate the efficacy of another promising pentacyclic triterpene (maslinic acid) to alleviate malaria and inflammation in general. Extensive in vivo and in vitro studies indicate that MA reduces inflammation by reducing lipopolysaccharides (LPS)-induced production of nitric oxide (NO) and INOS gene expression [132] Márquez et al. also indicated that MA reduces the production of interleukin-6

Many parasitic and metabolic diseases are built upon inflammatory processes. Ample indications exist that phytopharmaceuticals may moderate innumerable inflammatory mediators, govern the production and action of second messengers, direct the expression of transcription factors and key pro-inflammatory mechanisms [1, 2, 95, 115, 138–141]. The fundamental machinery of anti-inflammatory activity for AA in malarial may comprise: (i) anti-oxidative and radical scavenging;

*2D chemical structure of oleanolic acid (A) and maslinic acid (B) adapted from the PubMed database [134].*

*DOI: http://dx.doi.org/10.5772/intechopen.88731*

**7.3 Maslinic acid (MA) and oleanolic acid (OA)**

(IL-6) on peritoneal macrophages [132] (**Figure 5**).

**7.4 Anti-inflammatory effects of Asiatic acid (AA) in malaria**

**Figure 4.** *2D chemical structure of ursolic acid [131].*

*Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene… DOI: http://dx.doi.org/10.5772/intechopen.88731*

no research has been done on anti-inflammatory properties of this triterpene in malaria rats, several studies have evaluated anti-inflammatory properties on other experimental models in vivo and in vitro [134]. However, several studies have evaluated the anti-inflammatory properties of the compounds in in-vitro and in vivo. Tsai and Yin's reports indicate that UA and oleanolic acid (OA) alleviate inflammation through reduction of IL-6 and TNF-α [135]. Additionally, studies also validate the anti-inflammatory potency of UA by reducing the production of IL-2 and through activation of T-helper cells [136]. Liu et al., have shown that UA suppressed T cell responses including NF-kB inhibition at 25 mM while Bharata et al. demonstrated the efficacy against a lowers dose of UA IS enough to lower immune cells such as T-cells, B-cell, and macrophage activation. Apart from this, Xu et al. have shown that anti-inflammatory effects of UA are mediated through.

### **7.3 Maslinic acid (MA) and oleanolic acid (OA)**

Maslinic acid and oleanolic acid are two triterpenes widely abundant in olive trees and *Syzygium* spp. Among many pharmacological properties, these triterpenes have demonstrated efficacy against malaria [133]. The triterpenoids are generally highly hydrophobic, which reduces their bioavailability and efficacy. Sibiya et al. showed that once off application of an-OA patch reduces parasitemia and TNF-α plasma levels [137]. Exposure of the host to malaria activates macrophages which in turn induces production of TNF-α and then the release of other cytokines such as IL-6 which initiate inflammation. Reports also indicate the efficacy of another promising pentacyclic triterpene (maslinic acid) to alleviate malaria and inflammation in general. Extensive in vivo and in vitro studies indicate that MA reduces inflammation by reducing lipopolysaccharides (LPS)-induced production of nitric oxide (NO) and INOS gene expression [132] Márquez et al. also indicated that MA reduces the production of interleukin-6 (IL-6) on peritoneal macrophages [132] (**Figure 5**).

#### **7.4 Anti-inflammatory effects of Asiatic acid (AA) in malaria**

Many parasitic and metabolic diseases are built upon inflammatory processes. Ample indications exist that phytopharmaceuticals may moderate innumerable inflammatory mediators, govern the production and action of second messengers, direct the expression of transcription factors and key pro-inflammatory mechanisms [1, 2, 95, 115, 138–141]. The fundamental machinery of anti-inflammatory activity for AA in malarial may comprise: (i) anti-oxidative and radical scavenging;

**Figure 5.** *2D chemical structure of oleanolic acid (A) and maslinic acid (B) adapted from the PubMed database [134].*

*Parasitology and Microbiology Research*

**7.2 Ursolic acid**

immune system as shown by plasma levels of TNF-α and IFN-γ [59, 130]. A single injection dose of CCDO-EA (200 μmol/kg) lowered circulating levels of TNF-α and IFN-γ which improved mice survival and lowered inflammation [129]. Indeed, studies have indicated that the host's response to malaria is excess production of pro-inflammatory molecules which are thought to be central causes of inflammation in malaria.

Ursolic acid (3-hydroxy-urs-12-ene-28-oic acid, **Figure 4**) is triterpene which is widely distributed on different medicinal plants. UA has been shown to exhibit a number of pharmacological activities which include, anti-microbial [132], anti-malarial [133] and potent anti-inflammatory properties [134]. Although

**60**

**Figure 4.**

*2D chemical structure of ursolic acid [131].*

**Figure 3.**

*Chemical structure of a synthetic oleanolae derivative [129].*

(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 and IVCAM-1 [5, 143].

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 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].

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 Carrageenaninduced 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 possibly superoxide [O2 •<sup>−</sup>] [151]. Certainly, AA has been predicted by a computational model AutoDock v.3.05 to bind iNOS. This binding inhibits iNOS's strong affinity for arginine, exhibited as free energy binding (FEB) of −9.79 kcal.mol<sup>−</sup><sup>1</sup> [152–154].

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

**63**

**Author details**

**8. Conclusion**

Obadiah Moyo3

Tariroyashe Mpofu1

4 Pathcare, Namibia

Greanious Alfred Mavondo1

Mayibongwe Louis Mzingwane1

, Patience Musiwaro1

2 University of KwaZulu Natal, Durban, South Africa

5 University of Zimbabwe, Harare, Zimbabwe

provided the original work is properly cited.

6 Imagegate Diagnostics (PL), Bulawayo, Zimbabwe

\*Address all correspondence to: greanious.mavondo@nust.ac.zw

and Joy Mavondo6

tive treatment regimens for malaria are thus in the offing.

3 Chitungwiza General Hospital, Chitungwiza, Zimbabwe

*Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene…*

phagocytosis with parasite extrusion or destruction [157].

chloroquine-treated animals and non-treated controls [95].

will be up-regulation of CD36 in monocytes/macrophages for non-opsonic pRBC's

Credence of AA anti-inflammatory capacity in malarial pathophysiology has been shown. Indeed, the anti-inflammatory effect of AA has been reported in a murine malaria model where C-reactive protein was shown to be significantly reduced in infected transdermal AA administered animals as compared to infected

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 alterna-

\*, Blessing Nkazimulo Mkhwanazi2

, Francis Farai Chikuse4

, Rachael Dangarembizi1

1 National University of Science and Technology (NUST), Bulawayo, Zimbabwe

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

,

, Blessing Zambuko1

, Colline Rakabopa<sup>5</sup>

,

,

*DOI: http://dx.doi.org/10.5772/intechopen.88731*

*Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene… DOI: http://dx.doi.org/10.5772/intechopen.88731*

will be up-regulation of CD36 in monocytes/macrophages for non-opsonic pRBC's phagocytosis with parasite extrusion or destruction [157].

Credence of AA anti-inflammatory capacity in malarial pathophysiology has been shown. Indeed, the anti-inflammatory effect of AA has been reported in a murine malaria model where C-reactive protein was shown to be significantly reduced in infected transdermal AA administered animals as compared to infected chloroquine-treated animals and non-treated controls [95].
