Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner

Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum–infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)– and endothelial protein C receptor (EPCR)–binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood–brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1–dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.

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

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03495-9 ◽

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.

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Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

10.1101/2020.10.08.332007 ◽

2020 ◽

Author(s):

Alejandra Palomino-Antolin ◽

Paloma Narros-Fernández ◽

Víctor Farré-Alins ◽

Javier Sevilla-Montero ◽

Celine Decouty-Pérez ◽

...

Keyword(s):

Brain Injury ◽

Blood Brain Barrier ◽

Inflammatory Cytokines ◽

Nlrp3 Inflammasome ◽

Neurovascular Unit ◽

Time Dependent ◽

Brain Barrier ◽

Dependent Manner ◽

Dual Effect ◽

Blood Brain

AbstractBackground and purposePost-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit.MethodsWT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.ResultsWe identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.ConclusionsThese findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

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Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage

Open Life Sciences ◽

10.1515/biol-2021-0090 ◽

2021 ◽

Vol 16 (1) ◽

pp. 845-855

Author(s):

Huaxu Yu ◽

Bin He ◽

Xu Han ◽

Ting Yan

Keyword(s):

Kainic Acid ◽

Blood Brain Barrier ◽

Neuronal Damage ◽

Brain Barrier ◽

Protective Mechanism ◽

Dependent Manner ◽

Nissl Staining ◽

Microglia Cell ◽

Protein Levels ◽

Blood Brain

Abstract Rufinamide (RUF) is a structurally unique anti-epileptic drug, but its protective mechanism against brain injury remains unclear. In the present study, we validated how the RUF protected mice with kainic acid (KA)-induced neuronal damage. To achieve that, a mouse epilepsy model was established by KA intraperitoneal injection. After Nissl staining, although there was a significant reduction in Nissl bodies in mice treated with KA, 40, 80, and 120 mg/kg, RUF significantly reduced KA-induced neuronal damage, in a dose-dependent manner. Among them, 120 mg/kg RUF was most pronounced. Immunohistochemistry (IHC) and western blot analysis showed that RUF inhibited the IBA-1 overexpression caused by KA to block microglia cell overactivation. Further, RUF treatment partially reversed neuroinflammatory cytokine (IL-1β, TNFα, HMGB1, and NLRP3) overexpression in mRNA and protein levels in KA mice. Moreover, although KA stimulation inhibited the expression of tight junctions, RUF treatment significantly upregulated expression of tight junction proteins (occludin and claudin 5) in both mRNA and protein levels in the brain tissues of KA mice. RUF inhibited the overactivation of microglia, suppressed the neuroinflammatory response, and reduced the destruction of blood–brain barrier, thereby alleviating the excitatory nerve damage of the KA-mice.

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Flavonoid transport across RBE4 cells: A blood-brain barrier model

Cellular & Molecular Biology Letters ◽

10.2478/s11658-010-0006-4 ◽

2010 ◽

Vol 15 (2) ◽

Cited By ~ 61

Author(s):

Ana Faria ◽

Diogo Pestana ◽

Diana Teixeira ◽

Joana Azevedo ◽

Victor Freitas ◽

...

Keyword(s):

Blood Brain Barrier ◽

Cerebrovascular Diseases ◽

Brain Barrier ◽

Array Detector ◽

Dependent Manner ◽

Blood Brain ◽

Parkinson’S Diseases ◽

Blood Brain Barrier Model ◽

Immortalized Cell ◽

Barrier Model

AbstractThere is a growing interest in dietary therapeutic strategies to combat oxidative stress-induced damage to the Central Nervous System (CNS), which is associated with a number of pathophysiological processes, including Alzheimer’s and Parkinson’s diseases and cerebrovascular diseases. Identifying the mechanisms associated with phenolic neuroprotection has been delayed by the lack of information concerning the ability of these compounds to enter the CNS. The aim of this study was to evaluate the transmembrane transport of flavonoids across RBE-4 cells (an immortalized cell line of rat cerebral capillary endothelial cells) and the effect of ethanol on this transport. The detection and quantification of all of the phenolic compounds in the studied samples (basolateral media) was performed using a HPLC-DAD (Diode Array Detector). All of the tested flavonoids (catechin, quercetin and cyanidin-3-glucoside) passed across the RBE-4 cells in a time-dependent manner. This transport was not influenced by the presence of 0.1% ethanol. In conclusion, the tested flavonoids were capable of crossing this blood-brain barrier model.

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Penetration of the blood-brain barrier: enhancement of drug delivery and imaging by bacterial glycopeptides.

Journal of Experimental Medicine ◽

10.1084/jem.182.4.1037 ◽

1995 ◽

Vol 182 (4) ◽

pp. 1037-1043 ◽

Cited By ~ 28

Author(s):

B Spellerberg ◽

S Prasad ◽

C Cabellos ◽

M Burroughs ◽

P Cahill ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Parenchyma ◽

Brain Barrier ◽

Dependent Manner ◽

Pharmacological Agents ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

The Brain

The blood-brain barrier restricts the passage of many pharmacological agents into the brain parenchyma. Bacterial glycopeptides induce enhanced blood-brain barrier permeability when they are present in the subarachnoid space during meningitis. By presenting such glycopeptides intravenously, blood-brain barrier permeability in rabbits was enhanced in a reversible time- and dose-dependent manner to agents < or = 20 kD in size. Therapeutic application of this bioactivity was evident as enhanced penetration of the antibiotic penicillin and the magnetic resonance imaging contrast agent gadolinium-diethylene-triamine-pentaacetic acid into the brain parenchyma.

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Abstract 218: Pericytic Laminin Regulates Blood-Brain Barrier Integrity in an Age-Dependent Manner

Stroke ◽

10.1161/str.48.suppl_1.218 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yao Yao ◽

Jyoti Gautam ◽

Xuanming Zhang

Keyword(s):

Endothelial Cells ◽

Basement Membrane ◽

Blood Brain Barrier ◽

Vessel Density ◽

Brain Barrier ◽

Dependent Manner ◽

Vascular Integrity ◽

Blood Brain ◽

Age Dependent

Introduction: Laminin, a major component of the basement membrane, plays an important role in blood brain barrier (BBB) regulation. At the neurovascular unit, astrocytes, brain endothelial cells, and pericytes synthesize and deposit different laminin isoforms into the basement membrane. Previous studies from our laboratory showed that loss of astrocytic laminin induces age-dependent and region-specific BBB breakdown and intracerebral hemorrhage, suggesting a critical role of astrocytic laminin in vascular integrity maintenance. Laminin α4 (predominantly generated by endothelial cells) has been shown to regulate vascular integrity at embryonic/neonatal stage. The role of pericytic laminin in vascular integrity, however, remains elusive. Methods: We investigated the function of pericyte-derived laminin in vascular integrity using laminin conditional knockout mice. Specifically, laminin floxed mice were crossed with PDGFRβ-Cre line to generate mutants (PKO) with laminin deficiency in PDGFRβ + cells, which include both pericytes and vascular smooth muscle cells (vSMCs). To distinguish the contribution of pericyte- and vSMC-derived laminin, we also generated a vSMC-specific condition knockout line (TKO) by crossing the laminin floxed mice with Transgelin-Cre mice. In this study, mice of both genders on a C57Bl6 background were used. At least 5-6 animals were used in biochemical and histological analyses in this study. Results: Pericyte-derived laminin was abrogated in all PKO mice. However, only old but not young PKO mice showed signs of BBB breakdown and reduced vessel density, suggesting age-dependent changes. Consistent with these data, further mechanistic studies revealed reduced tight junction proteins, diminished AQP4 expression, and deceased pericyte coverage in old but not young PKO mice. In addition, neither BBB disruption nor decreased vessel density was observed in TKO mice, suggesting that these vascular defects are due to loss of pericyte- rather than vSMC-derived laminin. Conclusions: These results strongly suggest that pericyte-derived laminin active regulates BBB integrity and vessel density in an age-dependent manner. I would like this abstract to be considered for the Stroke Basic Science Award.

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Inflammatory Mediators Released by Brain Pericytes as Sensors and Effectors in Blood-Brain Barrier Dysfunction

Stem Cell Biology and Regenerative Medicine - Biology of Pericytes – Recent Advances ◽

10.1007/978-3-030-62129-2_6 ◽

2021 ◽

pp. 145-164

Author(s):

Shinya Dohgu ◽

Fuyuko Takata ◽

Yasufumi Kataoka

Keyword(s):

Blood Brain Barrier ◽

Inflammatory Mediators ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Brain Pericytes

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The role of inflammation in epileptogenesis

Acta Epileptologica ◽

10.1186/s42494-020-00024-y ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Fanwei Meng ◽

Lifen Yao

Keyword(s):

Blood Brain Barrier ◽

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Brain Barrier ◽

Keywords Epilepsy ◽

Model Studies ◽

Neuronal Excitation ◽

Blood Brain ◽

Pubmed Database ◽

Molecular Patterns

Abstract Epilepsy is a chronic neurological disorder that has an extensive impact on a patient’s life. Accumulating evidence has suggested that inflammation participates in the progression of spontaneous and recurrent seizures. Pro-convulsant incidences can stimulate immune cells, augment the release of pro-inflammatory cytokines, elicit neuronal excitation as well as blood-brain barrier (BBB) dysfunction, and finally trigger the generation or recurrence of seizures. Understanding the pathogenic roles of inflammatory mediators, including inflammatory cytokines, cells, and BBB, in epileptogenesis will be beneficial for the treatment of epilepsy. In this systematic review, we performed a literature search on the PubMed database using the following keywords: “epilepsy” or “seizures” or “epileptogenesis”, and “immunity” or “inflammation” or “neuroinflammation” or “damage-associated molecular patterns” or “cytokines” or “chemokines” or “adhesion molecules” or “microglia” or “astrocyte” or “blood-brain barrier”. We summarized the classic inflammatory mediators and their pathogenic effects in the pathogenesis of epilepsy, based on the most recent findings from both human and animal model studies.

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FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARγ Activation

International Journal of Molecular Sciences ◽

10.3390/ijms21030824 ◽

2020 ◽

Vol 21 (3) ◽

pp. 824 ◽

Cited By ~ 1

Author(s):

Yinghua Jiang ◽

Li Lin ◽

Ning Liu ◽

Qingzhi Wang ◽

Jing Yuan ◽

...

Keyword(s):

Dna Binding ◽

Blood Brain Barrier ◽

Binding Activity ◽

Brain Barrier ◽

Fibroblast Growth Factor 21 ◽

Mrna Levels ◽

Dependent Manner ◽

Dna Binding Activity ◽

Blood Brain ◽

Junction Protein

Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood–brain barrier (BBB) damage in T2DM mice via peroxisome proliferator-activated receptor gamma (PPARγ) activation in cerebral microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) model in T2DM mice as well as cultured human brain microvascular endothelial cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current study. We detected a significant reduction in PPARγ DNA-binding activity in the brain tissue and mRNA levels of BBB junctional proteins and PPARγ-targeting gene CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke induced a massive BBB leakage two days after stroke in T2DM mice compared to in their lean controls. Importantly, all abnormal changes were significantly prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro experimental results also demonstrated that rFGF21 protects against hyperglycemia plus interleukin (IL)-1β-induced transendothelial permeability through upregulation of junction protein expression in an FGFR1 activation and PPARγ activity elevation-dependent manner. Our data suggested that rFGF21 has strong protective effects on acute BBB leakage after diabetic stroke, which is partially mediated by increasing PPARγ DNA-binding activity and mRNA expression of BBB junctional complex proteins. Together with our previous investigations, rFGF21 might be a promising candidate for treating diabetic stroke.

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