scholarly journals Euterpe oleracea fruit (Açai)-enriched diet suppresses the development of experimental cerebral malaria induced by Plasmodium berghei (ANKA) infection

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Karen Renata Herculano Matos Oliveira ◽  
Marjorie Lujan Marques Torres ◽  
Nayara Kauffmann ◽  
Brenda Jaqueline de Azevedo Ataíde ◽  
Nívia de Souza Franco Mendes ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Plasmodium Berghei ◽  
Post Infection ◽  
Brain Barrier ◽  
Blue Dye ◽  
Euterpe Oleracea ◽  
Neurocognitive Deficits ◽  
Experimental Cerebral Malaria ◽  
Blood Brain

Abstract Background Cerebral malaria is one of the most severe complications attributed to protozoal infection by Plasmodium falciparum, gaining prominence in children mortality rates in endemic areas. This condition has a complex pathogenesis associated with behavioral, cognitive and motor sequels in humans and current antimalarial therapies have shown little effect in those aspects. Natural products with antioxidant and anti-inflammatory properties have become a valuable alternative therapeutic option in the treatment of distinct conditions. In this context, this study investigated the neuroprotective effect of Euterpe oleracea (açai) enriched diet during the development of experimental cerebral malaria induced by the inoculation of Swiss albino mice with Plasmodium berghei ANKA strain. Methods After Plasmodium infection, animals were maintained on a feeding with Euterpe oleracea enriched ration and parameters such as survival curve, parasitemia and body weight were routinely monitored. The present study has also evaluated the effect of açai-enriched diet on the blood-brain barrier leakage, histological alterations and neurocognitive impairments in mice developing cerebral malaria. Results Our results demonstrate that between 7th–19th day post infection the survival rate of the group treated with açai enriched ration was higher when compared with Plasmodium-infected mice in which 100% of mice died until the 11th days post-infection, demonstrating that açai diet has a protective effect on the survival of infected treated animals. The same was observed in the brain vascular extravasation, where Evans blue dye assays showed significantly less dye extravasation in the brains of Plasmodium-infected mice treated with açai enriched ration, demonstrating more preserved blood-brain barrier integrity. Açai-enriched diet also attenuate the histopathological alterations elicited by Plasmodium berghei infection. We also showed a decrease of the neurological impairments arising from the exposure of cerebral parenchyma in the group treated with açai diet, ameliorating motor and neuropsychiatric changes, analyzed through the SHIRPA protocol. Conclusion With these results, we conclude that the treatment with açai enriched ration decreased the mortality of infected animals, as well as protected the blood-brain barrier and the neurocognitive deficits in Plasmodium-infected animals.

scholarly journals Targeting the CD146/Galectin-9 axis protects the integrity of the blood–brain barrier in experimental cerebral malaria

2020 ◽  
Author(s):  
Hongxia Duan ◽  
Shuai Zhao ◽  
Jianquan Xiang ◽  
Chenhui Ju ◽  
Xuehui Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Immune Cells ◽  
Current Treatment ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Blood Brain ◽  
Infected Rbcs ◽  
Antiparasitic Drugs

AbstractCerebral malaria (CM) is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum, in which the destruction of the blood–brain barrier (BBB) is the main cause of death. However, increasing evidence has shown that antimalarial drugs, the current treatment for CM, do little to protect against CM-induced BBB damage. Therefore, a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM. The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation. Here, we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria (eCM). Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells (RBCs) and/or proinflammatory lymphocytes in CNS blood vessels, thereby promoting the disruption of BBB integrity. Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes. Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM, such as limb paralysis, brain vascular leakage, and death. In addition, AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM. Taken together, our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.

scholarly journals Beta Interferon Suppresses the Development of Experimental Cerebral Malaria

2011 ◽  
Vol 79 (4) ◽  
pp. 1750-1758 ◽  
Author(s):  
Craig N. Morrell ◽  
Kalyan Srivastava ◽  
AnneMarie Swaim ◽  
M. Teresa Lee ◽  
Jun Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Vascular Inflammation ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Beta Interferon ◽  
Cxcr3 Expression ◽  
Blood Brain ◽  
The Brain

ABSTRACTCerebral malaria (CM) is a major complication ofPlasmodium falciparuminfection, particularly in children. The pathogenesis of cerebral malaria involves parasitized red blood cell (RBC)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. Therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. Beta interferon (IFN-β) has been used in the treatment of diseases, such as multiple sclerosis (MS) but has not yet been explored in the treatment of CM. Therefore, we sought to determine whether IFN-β also limits disease progression in experimental cerebral malaria (ECM).Plasmodium berghei-infected mice treated with IFN-β died later and showed increased survival, with improved blood-brain barrier function, compared to infected mice. IFN-β did not alter systemic parasitemia. However, we identified multiple action sites that were modified by IFN-β administration.P. bergheiinfection resulted in increased expression of chemokine (C-X-C motif) ligand 9 (CXCL9) in brain vascular endothelial cells that attract T cells to the brain, as well as increased T-cell chemokine (C-X-C motif) receptor 3 (CXCR3) expression. The infection also increased the cellular content of intercellular adhesion molecule 1 (ICAM-1), a molecule important for attachment of parasitized RBCs to the endothelial cell. In this article, we report that IFN-β treatment leads to reduction of CXCL9 and ICAM-1 in the brain, reduction of T-cell CXCR3 expression, and downregulation of serum tumor necrosis factor alpha (TNF-α). In addition, IFN-β-treatedP. berghei-infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN-β has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival.

scholarly journals Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages

2021 ◽  
Author(s):  
Angelika Hoffmann ◽  
Jessica Jin ◽  
Mame Aida ◽  
Chi Ho Wai ◽  
Sanjib Mohanty ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Fatal Outcome ◽  
Brain Barrier ◽  
Brain Swelling ◽  
Experimental Cerebral Malaria ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model.

Fenozyme Protects the Integrity of the Blood–Brain Barrier against Experimental Cerebral Malaria

Nano Letters ◽  
2019 ◽  
Vol 19 (12) ◽  
pp. 8887-8895 ◽  
Author(s):  
Shuai Zhao ◽  
Hongxia Duan ◽  
Yili Yang ◽  
Xiyun Yan ◽  
Kelong Fan
Keyword(s):  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Blood Brain

scholarly journals S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Robyn E. Elphinstone ◽  
Rickvinder Besla ◽  
Eric A. Shikatani ◽  
Ziyue Lu ◽  
Alfred Hausladen ◽  
...  
Keyword(s):  
T Cell ◽  
Cerebral Malaria ◽  
Clinical Outcomes ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

ABSTRACT Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P < 0.0001), despite higher parasite burdens (P < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4+ and CD8+ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.

scholarly journals Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8+T Cells with Different Specificities

2014 ◽  
Vol 82 (11) ◽  
pp. 4854-4864 ◽  
Author(s):  
Chek Meng Poh ◽  
Shanshan W. Howland ◽  
Gijsbert M. Grotenbreg ◽  
Laurent Rénia
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Synergistic Effects ◽  
Brain Barrier ◽  
High Dose ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Blood Brain

ABSTRACTCD8+T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced byPlasmodium bergheiANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8+epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8+T cells. Induction and functionality of these specific CD8+T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8+T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-γ], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrierin vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8+T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8+T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8+T cell responses that are involved in ECM.

scholarly journals Experimental Cerebral Malaria Pathogenesis—Hemodynamics at the Blood Brain Barrier

2014 ◽  
Vol 10 (12) ◽  
pp. e1004528 ◽  
Author(s):  
Adéla Nacer ◽  
Alexandru Movila ◽  
Fabien Sohet ◽  
Natasha M. Girgis ◽  
Uma Mahesh Gundra ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Blood Brain
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