Mild hyperhomocysteinemia induces blood–brain barrier dysfunction but not neuroinflammation in the cerebral cortex and hippocampus of wild-type mice

This study explored the potential effects of mild hyperhomocysteinemia (HHcy) on the blood–brain barrier (BBB) and neuroinflammation. Seven-week-old male wild-type C57BL/6 mice were fed normal mouse chow (the control group) or a methionine-enriched diet (the HHcy group) for 14 weeks. Mice in the HHcy group exhibited a slight increase in serum Hcy levels (13.56 ± 0.61 μmol/L). Activation of the ERK signaling pathway, up-regulation of matrix metalloproteinase-9 (MMP-9), and degradation of tight junction proteins (occludin and claudin-5) were observed in both the cerebral cortex and hippocampus of mice with mild HHcy. However, microglia were not activated and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were not changed in either the cerebral cortex or hippocampus of mice with mild HHcy. Moreover, the signaling activity of STAT3 also did not differ significantly between the two groups. These findings demonstrate that the BBB is highly vulnerable to homocysteine insult. Even a slight increase in serum homocysteine levels up-regulates MMP-9 expression and disrupts the BBB integrity. Meanwhile, microglia activation or the STAT3 pathway might not contribute to the effects of mild HHcy on the brain.

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Tumour necrosis factor-α mediates blood—brain barrier damage in HIV-1 infection of the central nervous system

Mediators of Inflammation ◽

10.1155/s0962935192000292 ◽

1992 ◽

Vol 1 (3) ◽

pp. 191-196 ◽

Cited By ~ 6

Author(s):

M. K. Sharief ◽

M. Ciardi ◽

E. J. Thompson ◽

F. Sorice ◽

F. Rossi ◽

...

Keyword(s):

Blood Brain Barrier ◽

Tumour Necrosis ◽

Brain Barrier ◽

Tumour Necrosis Factor Α ◽

Blood Brain ◽

Tnf Α ◽

Factor Α ◽

Hiv 1 ◽

Blood Brain Barrier Damage ◽

Necrosis Factor

The pathogenesis of brain inflammation and damage by human immunodeficiency virus (HIV) infection is unclear. Because blood–brain barrier damage and impaired cerebral perfusion are common features of HIV-1 infection, we evaluated the role of tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in mediating disruption of the blood–brain barrier. Levels of TNF-α were more elevated in cerebrospinal fluid (CSF) than in serum of HIV-1 infected patients and were mainly detected in those patients who had neurologic involvement. Intrathecal TNF-α levels correlated with signs of blood–brain barrier damage, manifested by high CSF to serum albumin quotient, and with the degree of barrier impairment. In contrast, intrathecal IL-1β levels did not correlate with blood-brain barrier damage in HIV-1 infected patients. TNF-α seems to be related to active neural inflammation and to blood–brain barrier damage. The proinflammatory effects of TNF-α in the nervous system are dissociated from those of IL-1β.

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Metabolic-cytokine responses to a second immunological challenge with LPS in mice withT. gondiiinfection

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.3.e439 ◽

1998 ◽

Vol 274 (3) ◽

pp. E439-E445 ◽

Cited By ~ 3

Author(s):

D. Arsenijevic ◽

L. Girardier ◽

J. Seydoux ◽

J. C. Pechere ◽

I. Garcia ◽

...

Keyword(s):

Blood Brain Barrier ◽

Chronic Phase ◽

Serum Levels ◽

Brain Barrier ◽

Blood Brain ◽

Tnf Α ◽

The Central Nervous System ◽

Lower Ratio ◽

Factor Α ◽

Partial Weight

Injection of 10 cysts of Toxoplasma gondii (Me49 strain) into Swiss Webster mice results in 1) an acute phase of infection lasting for 2–3 wk, characterized by weight loss, and 2) a chronic phase in which surviving mice show either partial weight recovery (Gainers) or persistent, although stable, cachexia (Nongainers). In response to a second immunological stimulation with lipopolysaccharide (LPS) in the chronic phase of the infection, it is shown that 1) the increase in energy expenditure was more prolonged in both groups of infected mice than in controls, 2) the intensity and duration of hypophagia were also differently affected with Nongainers > Gainers > controls, and 3) the infected mice had higher serum levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-10 and a lower ratio of IL-10 to TNF-α than controls. In contrast, serum IL-4 increased to the same level in all three groups. Evaluation of the permeability of the blood-brain barrier by intravenous injection of Evans blue revealed a marked staining in the brain of only the infected Nongainers. Taken together, these results indicate that, in mice with chronic toxoplasmosis, a second nonspecific challenge (with LPS) exacerbates the hypophagic and hypermetabolic states, the latter being associated with hyperresponsiveness in TNF-α and IL-10 production. Furthermore, the greater exacerbation of the hypophagic state in mice showing persistent cachexia may be due to a preexisting higher permeability of the blood-brain barrier, which would allow a greater access of plasma-borne cytokines and/or other neuroimmunologically active substances to the central nervous system.

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Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding

Clinical and Experimental Pharmacology and Physiology ◽

10.1111/1440-1681.12032 ◽

2012 ◽

Vol 40 (1) ◽

pp. 45-52 ◽

Cited By ~ 23

Author(s):

Ryusuke Takechi ◽

Susan Galloway ◽

Menuka M Pallebage-Gamarallage ◽

Virginie Lam ◽

Satvinder S Dhaliwal ◽

...

Keyword(s):

Blood Brain Barrier ◽

Saturated Fat ◽

Brain Barrier ◽

Wild Type ◽

Cholesterol Feeding ◽

Barrier Dysfunction ◽

Blood Brain

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Corrigendum

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15619790 ◽

2016 ◽

Vol 36 (2) ◽

pp. 457-457

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Signaling Pathway ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Tnf Α

The TNF-α/NF-κB signaling pathway has a key role in methamphetamine–induced blood–brain barrier dysfunction Vanessa Coelho-Santos, Ricardo A Leitão, Filipa L Cardoso, Inês Palmela, Manuel Rito, Marcos Barbosa, Maria A Brito, Carlos A Fontes-Ribeiro and Ana P Silva Journal of Cerebral Blood Flow & Metabolism 2015; 35: 1260–1271 .

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.59 ◽

2015 ◽

Vol 35 (8) ◽

pp. 1260-1271 ◽

Cited By ~ 40

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.

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Interleukin-8 Released into the Cerebrospinal Fluid after Brain Injury is Associated with Blood–Brain Barrier Dysfunction and Nerve Growth Factor Production

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199703000-00005 ◽

1997 ◽

Vol 17 (3) ◽

pp. 280-289 ◽

Cited By ~ 173

Author(s):

Thomas Kossmann ◽

Philip F. Stahel ◽

Philipp M. Lenzlinger ◽

Heinz Redl ◽

Rolf W. Dubs ◽

...

Keyword(s):

Nerve Growth Factor ◽

Brain Injury ◽

Growth Factor ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Nerve Growth ◽

Blood Brain ◽

Cultured Astrocytes ◽

Factor Α

Interleukin (IL) 8 was measured in CSF of 14 patients with severe traumatic brain injury. IL-8 levels were significantly higher in CSF (up to 8,000 pg/ml) than serum (up to 2,400 pg/ml) (p < 0.05), suggesting intrathecal production. Maximal IL-8 values in CSF correlated with a severe dysfunction of the blood–brain barrier. Nerve growth factor (NGF) was detected in CSF of 7 of 14 patients (range of maximal NGF: 62–12,130 pg/ml). IL-8 concentrations were significantly higher in these patients than in those without NGF (p < 0.01). CSF containing high IL-8 (3,800–7,900 pg/ml) induced greater NGF production in cultured astrocytes (202–434 pg/ml) than samples with low IL-8 (600–1,000 pg/ml), which showed a smaller NGF increase (0–165 pg/ml). Anti-IL-8 antibodies strongly reduced (52–100%) the release of NGF in the group of high IL-8, whereas in the group with low IL-8, this effect was lower (0–52%). The inability of anti-IL-8 antibodies to inhibit the synthesis of NGF completely may depend on cytokines like tumor necrosis factor α and IL-6 found in these CSF samples, which may act in association with IL-8. Thus, IL-8 may represent a pivotal cytokine in the pathology of brain injury.

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Free circulating ICAM-1 in serum and cerebrospinal fluid of HIV-1 infected patients correlate with TNF-α and blood-brain barrier damage

Mediators of Inflammation ◽

10.1155/s0962935192000486 ◽

1992 ◽

Vol 1 (5) ◽

pp. 323-328 ◽

Cited By ~ 4

Author(s):

M. K. Sharief ◽

M. Ciardi ◽

M. A. Noori ◽

E. J. Thompson ◽

A. Salotti ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Blood Brain ◽

Tnf Α ◽

Factor Α ◽

Hiv 1 ◽

Blood Brain Barrier Damage

The mechanism for the initiation of blood-brain barrier damage and intrathecal inflammation in patients infected with the human immunodeficiency virus (HIV) is poorly understood. We have recently reported that tumour necrosis factor-α (TNF-α) mediates active neural inflammation and blood-brain barrier damage in HIV-1 infection. Stimulation of endothelial cells by TNF-α induces the expression of intercellular adhesion molecule-1 (ICAM-1), which is an important early marker of immune activation and response. We report herein for the first time the detection of high levels of free circulating ICAM-1 in serum and cerebrospinal fluid of patients with HIV-1 infection. Free circulating ICAM-1 in these patients correlated with TNF-α concentrations and with the degree of blood-brain barrier damage and were detected predominantly in patients with neurologic involvement. These findings have important implications for the understanding and investigation of the intrathecal inflammatory response in HIV-1 infection.

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