The immune system mediates blood-brain barrier damage; possible implications for pathophysiology of neuropsychiatric illnesses

1995 ◽  
Vol 7 (4) ◽  
pp. 114-121 ◽  
Author(s):  
Y.D. Van Der Werf ◽  
M.J.L. De Jongste ◽  
G.J. Ter Horst
Keyword(s):  
Myocardial Infarction ◽  
Immune System ◽  
Blood Brain Barrier ◽  
Immune Activation ◽  
Inflammatory Cytokine ◽  
Brain Barrier ◽  
Necrosis Factor Alpha ◽  
Blood Brain ◽  
Tnf Α ◽  
The Brain

SummaryIn this investigation the effects of immune activation on the brain are characterized. In order to study this, we used a model for chronic immune activation, the myocardial infarction, and intravenous injections with the pro-inflammatory cytokine Tumour Necrosis Factor alpha (TNF-α). The incentive for this study is the observation that myocardial infarction is accompanied by behavioural and neuronal abnormalities. The effects of myocardial infarction on the brain and its functioning are widespread. In order to examine the mechanism through which this interaction occurs, a group of rats underwent an experimentally induced myocardial infarction whereafter immunohistochemistry was performed on slices of the brain. This experiment revealed regional serum protein extravasation, pointing to leakage of the blood-brain barrier. This process occurred in certain cortical, subcortical and hindbrain areas in discrete patches. The leakage was co-localized with the expression of the immune activation marker ICAM-1. A second group of rats was therefore injected with TNF-α, a major pro-inflammatory cytokine, to assess the involvement of the immune system in the effects shown. This procedure rendered the same results. It is concluded that myocardial infarction may interfere with the integrity of the blood-brain barrier and possibly with brain functioning through activation of the immune system. The relevance for pathophysiological processes is discussed.

scholarly journals Age-Associated Changes in the Immune System and Blood–Brain Barrier Functions

2019 ◽  
Vol 20 (7) ◽  
pp. 1632 ◽  
Author(s):  
Michelle Erickson ◽  
William Banks
Keyword(s):  
Central Nervous System ◽  
Immune System ◽  
Blood Brain Barrier ◽  
Neurological Disorders ◽  
Brain Barrier ◽  
Immune Functions ◽  
Blood Brain ◽  
The Brain ◽  
Brain Barriers

Age is associated with altered immune functions that may affect the brain. Brain barriers, including the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB), are important interfaces for neuroimmune communication, and are affected by aging. In this review, we explore novel mechanisms by which the aging immune system alters central nervous system functions and neuroimmune responses, with a focus on brain barriers. Specific emphasis will be on recent works that have identified novel mechanisms by which BBB/BCSFB functions change with age, interactions of the BBB with age-associated immune factors, and contributions of the BBB to age-associated neurological disorders. Understanding how age alters BBB functions and responses to pathological insults could provide important insight on the role of the BBB in the progression of cognitive decline and neurodegenerative disease.

scholarly journals Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

2013 ◽  
Vol 57 (9) ◽  
pp. 4336-4342 ◽  
Author(s):  
Liang Jin ◽  
Roger L. Nation ◽  
Jian Li ◽  
Joseph A. Nicolazzo
Keyword(s):  
Blood Brain Barrier ◽  
Bacterial Species ◽  
Specific Effect ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

ABSTRACTThe aim of this study was to usein vitroandin vivomodels to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS fromPseudomonas aeruginosa, the brain-to-plasma ratio of [14C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS fromSalmonella enterica, LPS fromP. aeruginosahad no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P> 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS fromP. aeruginosaorS. entericaand claudin-5 expression was measured by Western blotting.S. entericaLPS significantly (P< 0.05) reduced claudin-5 expression at a concentration of 7.5 μg/ml. In contrast,P. aeruginosaLPS decreased (P< 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 μg/ml). Coadministration of therapeutic concentrations of colistin ameliorated theS. entericaLPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least betweenP. aeruginosaandS. enterica, and can be ameliorated by colistin.

scholarly journals Activation of PKC Isoform βI at the Blood–Brain Barrier Rapidly Decreases P-Glycoprotein Activity and Enhances Drug Delivery to the Brain

2010 ◽  
Vol 30 (7) ◽  
pp. 1373-1383 ◽  
Author(s):  
Robert R Rigor ◽  
Brian T Hawkins ◽  
David S Miller
Keyword(s):  
Rat Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Capillaries ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Tnf Α ◽  
The Brain

P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood–brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-α-induced reduction of P-glycoprotein activity was prevented by a PKCβI/II inhibitor, LY333531, and mimicked by a PKCβI/II activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCβI, but not PKCβII. Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [3H]-verapamil without compromising tight junction integrity. Thus, PKCβI activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCβI at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain.

scholarly journals Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Goodwell Nzou ◽  
Robert T. Wicks ◽  
Nicole R. VanOstrand ◽  
Gehad A. Mekky ◽  
Stephanie A. Seale ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokine ◽  
Disease Modeling ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Dynamic Component ◽  
Blood Brain ◽  
Anti Inflammatory ◽  
The Brain

AbstractThe blood-brain barrier (BBB) is a dynamic component of the brain-vascular interface that maintains brain homeostasis and regulates solute permeability into brain tissue. The expression of tight junction proteins between adjacent endothelial cells and the presence of efflux proteins prevents entry of foreign substances into the brain parenchyma. BBB dysfunction, however, is evident in many neurological disorders including ischemic stroke, trauma, and chronic neurodegenerative diseases. Currently, major contributors to BBB dysfunction are not well understood. Here, we employed a multicellular 3D neurovascular unit organoid containing human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes and neurons to model the effects of hypoxia and neuroinflammation on BBB function. Organoids were cultured in hypoxic chamber with 0.1% O2 for 24 hours. Organoids cultured under this hypoxic condition showed increased permeability, pro-inflammatory cytokine production, and increased oxidative stress. The anti-inflammatory agents, secoisolariciresinol diglucoside and 2-arachidonoyl glycerol, demonstrated protection by reducing inflammatory cytokine levels in the organoids under hypoxic conditions. Through the assessment of a free radical scavenger and an anti-inflammatory endocannabinoid, we hereby report the utility of the model in drug development for drug candidates that may reduce the effects of ROS and inflammation under disease conditions. This 3D organoid model recapitulates characteristics of BBB dysfunction under hypoxic physiological conditions and when exposed to exogenous neuroinflammatory mediators and hence may have potential in disease modeling and therapeutic development.

Effect of endotoxin on expression of TNF receptors and transport of TNF-α at the blood-brain barrier of the rat

2002 ◽  
Vol 283 (5) ◽  
pp. E899-E908 ◽  
Author(s):  
B. Osburg ◽  
C. Peiser ◽  
D. Dömling ◽  
L. Schomburg ◽  
Y. T. Ko ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Blood Brain ◽  
Permeability Surface ◽  
Tnf Α ◽  
Area Product ◽  
Brain Microvessel ◽  
The Brain ◽  
Necrosis Factor

The transport mechanism mediating brain uptake of tumor necrosis factor (TNF)-α has been studied. When 125I-labeled rat TNF-α was used in internal carotid artery perfusions in rats, the cytokine showed transcytosis through the blood-brain barrier in intact form (permeability-surface area product 0.34 ± 0.13 μl · min−1 · g−1). Uptake was inhibited by low nanomolar concentrations of unlabeled rat TNF-α. Human TNF-α, which does not interact with the p80 TNF receptor in rodents, showed no brain uptake. mRNA expression of both p60 and p80 receptors could be demonstrated in native brain microvessel preparations. These transcripts increased to 149% (p60) and 127% (p80) of control 4 h after a systemic immune stimulation (2 mg/kg bacterial endotoxin ip). Lipopolysaccharide treatment did not alter the rate of brain uptake of TNF-α measured between 4 and 24 h later. In conclusion, a receptor-mediated mechanism is responsible for the transcytosis of TNF-α. Saturable transport, requiring the p80 receptor, occurs at concentrations encountered under pathophysiological conditions and therefore constitutes a relevant mechanism of communication between the immune system and the brain.

scholarly journals The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

2015 ◽  
Vol 35 (8) ◽  
pp. 1260-1271 ◽  
Author(s):  
Vanessa Coelho-Santos ◽  
Ricardo A Leitão ◽  
Filipa L Cardoso ◽  
Inês Palmela ◽  
Manuel Rito ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Animal Studies ◽  
Negative Impact ◽  
Barrier Properties ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Necrosis Factor Alpha ◽  
Blood Brain ◽  
Tnf Α

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF- α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF- κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF- α/NF- κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF- α and subsequent activation of NF- κB pathway culminating in barrier dysfunction.

scholarly journals Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women

2018 ◽  
Vol 43 (7) ◽  
pp. 733-741 ◽  
Author(s):  
Matheus Uba Chupel ◽  
Luciele Guerra Minuzzi ◽  
Guilherme Furtado ◽  
Mário Leonardo Santos ◽  
Eef Hogervorst ◽  
...  
Keyword(s):  
Exercise Training ◽  
Blood Brain Barrier ◽  
Elderly Women ◽  
Neuron Specific Enolase ◽  
Brain Barrier ◽  
Taurine Supplementation ◽  
Necrosis Factor Alpha ◽  
Blood Brain ◽  
Tnf Α ◽  
Peripheral Markers

Immunosenescence contribute to increase the blood-brain barrier (BBB) permeability, leading cognitive impairment and neurodegeneration. Thus, we investigated the anti-inflammatory effect of exercise and taurine supplementation on peripheral markers of BBB, inflammation, and cognition of elderly women. Forty-eight elderly women (age, 83.58 ± 6.9 years) participated in the study, and were allocated into combined exercise training (CET: n = 13), taurine supplementation (TAU: n = 12), exercise training associated with taurine (CET+TAU: n = 11), or control (CG: n = 12) groups. Exercise was applied twice a week (multi-modal exercise). Taurine ingestion was 1.5 g., once a day. Participants were evaluated before and after 14-weeks of intervention. Plasma levels of interleukin (IL)-1β, IL-1ra, IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNF-α), and serum concentration of S100β and neuron specific enolase (NSE) were determined. The mini mental state examination (MMSE) was also applied. Concentrations of S100β were maintained in all intervention groups, while a subtle increase in the CG was found. NSE levels increased only in TAU group (p < 0.05). CET reduced TNF-α, IL-6, and IL-1β/IL-1ra, IL-6/IL10, and TNF-α/IL-10 ratios (p < 0.05). TAU decreased the IL-1β/IL-1ra ratio (p < 0.05). MMSE score increased only in the CET+TAU group (p < 0.05). Multiple regression analysis showed that there was a trend for changes in IL-1β and the Charlson Comorbidity Index to be independently associated with changes in S100β. Exercise and taurine decreased inflammation, and maintained the BBB integrity in elderly women. Exercise emerged as an important tool to improve brain health even when started at advanced ages.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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