Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria

Crowley, Valerie M.; Ayi, Kodjo; Lu, Ziyue; Liby, Karen T.; Sporn, Michael B.; Kain, Kevin C.

doi:10.1186/s12936-017-2109-0

Cited by 20 publications

(18 citation statements)

References 76 publications

(92 reference statements)

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“…Other therapeutic agents that increase Ang1 expression also prevent BBB leak and improve survival in ECM. Mice treated with the ethyl amide of a synthetic oleanane triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-EA), had increased Ang1, reduced Ang2 and Ang2:Ang1 ratio, and this was associated with improved BBB integrity ( 208 ). Similarly, treatment of malaria infected mice with the PPAR-γ agonist rosiglitazone in combination with artesunate at the onset of neurological symptoms achieved higher plasma and brain levels of Ang1 and a lower Ang2:Ang1 ratio compared to mice treated with artesunate alone.…”

Section: Therapeutic Interventions Targeting the Ang/tie Axismentioning

confidence: 99%

Endothelial Activation: The Ang/Tie Axis in Sepsis

et al. 2018

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Sepsis, a dysregulated host response to infection that causes life-threatening organ dysfunction, is a highly heterogeneous syndrome with no specific treatment. Although sepsis can be caused by a wide variety of pathogenic organisms, endothelial dysfunction leading to vascular leak is a common mechanism of injury that contributes to the morbidity and mortality associated with the syndrome. Perturbations to the angiopoietin (Ang)/Tie2 axis cause endothelial cell activation and contribute to the pathogenesis of sepsis. In this review, we summarize how the Ang/Tie2 pathway is implicated in sepsis and describe its prognostic as well as therapeutic utility in life-threatening infections.

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Section: Therapeutic Interventions Targeting the Ang/tie Axismentioning

confidence: 99%

Endothelial Activation: The Ang/Tie Axis in Sepsis

et al. 2018

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“…During CM, dysfunction of the ECs may occur due to adhesion of iRBCs to ECs, the local proinflammatory cytokine response, and increased coagulation of the blood in the microvasculature leading to cerebrovascular constriction ( Figure 2). Synthetic oleanane triterpenoids have been shown to reduce plasma levels of the cytokines IL-10, TNF, and IFN-γ, thereby enhancing the integrity of the BBB during ECM [51]. Recently, Barker et al [52] have implicated micro RNA in the activation of ECs (Figure 4).…”

Section: Factors Governing Endothelial Dysfunction In CMmentioning

confidence: 99%

Blood–Brain Barrier in Cerebral Malaria: Pathogenesis and Therapeutic Intervention

Nishanth

Schlüter

2019

Trends in Parasitology

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Cerebral malaria is a life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The growing problem of drug resistance and the dearth of new antiparasitic drugs are a serious threat to the antimalaria treatment regimes. Studies on humans and the murine model have implicated the disruption of the blood-brain barrier (BBB) in the lethal course of the disease. Therefore, efforts to alleviate the BBB dysfunction could serve as an adjunct therapy. Here, we review the mechanisms associated with the disruption of the BBB. In addition, we discuss the current, still limited, knowledge on the contribution of different cell types, microparticles, and the kynurenine pathway in the regulation of BBB dysfunction, and how these molecules could be used as potential new therapeutic targets. Cerebral Malaria-Clinical Significance and the Differences between Murine and Human Studies Cerebral malaria (CM) is a severe neurological syndrome of human malaria caused by the parasite Plasmodium falciparum (Pf) affecting mainly children in sub-Saharan Africa and adults in Asia. The complications of CM include clouding of consciousness, cerebral seizures, and coma, and may lead to the death of the infected individual. According to the 2018 WHO World Malaria Report for 2017, 435 000 patients died of malaria, with CM accounting for 90% of the deaths. About a quarter of surviving patients suffer from long-term neurological and cognitive deficits such as behavioral abnormality, epilepsy, and impaired motor functions [1,2]. Over the years, quinine and artemisinin compounds (see Glossary) have been used for the treatment of severe malaria. The use of these drugs has led to the emergence of resistant strains [3,4]. The problem of drug resistance is ever growing, and novel therapeutic strategies need to be developed, particularly those targeting the host or host-pathogen interaction. Understanding the underlying mechanisms leading to the development of CM would aid in the identification of potential new therapeutic targets. One major limitation of human CM studies is that a detailed analysis of the intracerebral pathogenesis and pathology can be conducted mainly postmortem. Therefore, CM is experimentally studied using a mouse model known as experimental cerebral malaria (ECM). Although Plasmodium berghei ANKA (PbA)-induced ECM recapitulates some of the features of human CM, the disease pathology differs considerably. While human CM is characterized by sequestration of infected red blood cells (iRBCs) to the cerebral microvasculature, with minute inflammatory changes in the brain, murine ECM shows little or no intracerebral sequestration of iRBCs but a prominent proinflammatory cytokine response in the brain. Moreover, human postmortem reports revealed no intracerebral accumulation of CD8 + T cells, whereas intracerebral accumulation of CD8 + T cells is essential for the development of ECM (reviewed in detail by White et al. [5]). These differences need to be considered while translating murine studies to human malaria....

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

Section: Synthetic Oleanolic (So) Pentacyclic Triterpenes Derivativesmentioning

confidence: 99%

“…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.…”

Section: Synthetic Oleanolic (So) Pentacyclic Triterpenes Derivativesmentioning

confidence: 99%

“…Although Figure 3. Chemical structure of a synthetic oleanolae derivative [129]. 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].…”

Section: Ursolic Acidmentioning

confidence: 99%

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Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene Phytotherapeutics

Mavondo¹,

Mkhwanazi²,

Mzingwane³

et al. 2020

Parasitology and Microbiology Research

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Malaria driven pathophysiology inimically conjoined to systemic inflammation response cascade in a vicious feed-forward cycle destined to a terrible debilitation or demise of the host. The Plasmodium parasite initiates physiological changes when it is transmitted into the human host by intermediate host and vector. Sporozoites injection elicits immunological and inflammatory response suppression facilitating movement into the blood stream undetected, destined to hepatocyte. Subsequently, hepatocyte invasion culminates in intracellular growth and conversion of the parasites rapturing hepatocytes releasing merozoites into the extrahepatic circulation. Inflammatory and immunological response initiation results in overt malarial disease symptoms. Initially, inflammatory response alleviates and curtails infection. Activation of leukocytes, lymphocytes, monocytes, and phagocytes secretes inflammatory mediators, chemokines, cytokines cytoadhering molecules which accelerate infection patency. Hormonal processes influence disease tolerance without necessarily interfering with parasitemia. Current treatment is anti-parasitic. Phytotherapeutic intervention in malaria is anti-parasitic and anti-disease effects that terminate the vicious cycle and alleviating disease. The phytochemicals, in malarial experimental and clinical work, include asiatic acid, maslinic acid, oleanolic acid, and inflammatory and immunological aberrations evolving in malaria and the effects of phytochemical therapeutics in the alleviation of the disease to enable leverage of future treatment regimens through harnessing existing plants materials is explored.

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Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria

Cited by 20 publications

References 76 publications

Endothelial Activation: The Ang/Tie Axis in Sepsis

Endothelial Activation: The Ang/Tie Axis in Sepsis

Blood–Brain Barrier in Cerebral Malaria: Pathogenesis and Therapeutic Intervention

Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene Phytotherapeutics

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