Good post.

Inflammatory Response In The Brain Reduced By Plant Flavonoid
Article Date: 21 May 2008 - 3:00 PDT

Researchers at the University of Illinois report this week that a
plant compound found in abundance in celery and green peppers can
disrupt a key component of the inflammatory response in the brain. The
findings have implications for research on aging and diseases such as
Alzheimer's and multiple sclerosis.

The study appears this week in Proceedings of the National Academy of
Sciences.

Inflammation can be a blessing or a blight. It is a critical part of
the body's immune response that in normal circumstances reduces injury
and promotes healing. When it goes awry, however, the inflammatory
response can lead to serious physical and mental problems.

Inflammation plays a key role in many neurodegenerative diseases and
also is implicated in the cognitive and behavioral impairments seen in
aging.

The new study looked at luteolin (LOO-tee-OH-lin), a plant flavonoid
known to impede the inflammatory response in several types of cells
outside the central nervous system. The purpose of the study was to
determine if luteolin could also reduce inflammation in the brain,
said animal sciences professor and principal investigator Rodney
Johnson.

"One of the questions we were interested in is whether something like
luteolin, or other bioactive food components, can be used to mitigate
age-associated inflammation and therefore improve cognitive function
and avoid some of the cognitive deficits that occur in aging," Johnson
said.

The researchers first studied the effect of luteolin on microglia.
These brain cells are a key component of the immune defense. When
infection occurs anywhere in the body, microglia respond by producing
inflammatory cytokines, chemical messengers that act in the brain to
orchestrate a whole-body response that helps fight the invading
microorganism.

This response is associated with many of the most obvious symptoms of
illness: sleepiness, loss of appetite, fever and lethargy, and
sometimes a temporary diminishment of learning and memory.
Neuroinflammation can also lead some neurons to self-destruct, with
potentially disastrous consequences if it goes too far.

Graduate research assistant Saebyeol Jang studied the inflammatory
response in microglial cells. She spurred inflammation by exposing the
cells to lipopolysaccharide (LPS), a component of the cell wall of
many common bacteria.

Those cells that were also exposed to luteolin showed a significantly
diminished inflammatory response. Jang showed that luteolin was
shutting down production of a key cytokine in the inflammatory
pathway, interleukin-6 (IL-6). The effects of luteolin exposure were
dramatic, resulting in as much as a 90 percent drop in IL-6 production
in the LPS-treated cells.

"This was just about as potent an inhibition as anything we had seen
previously," Johnson said.

But how was luteolin inhibiting production of IL-6"

Jang began by looking at a class of proteins involved in intracellular
signaling, called transcription factors, which bind to specific
"promoter" regions on DNA and increase their transcription into RNA
and translation into proteins.

Using electromobility shift assays, which measure the binding of
transcription factors to DNA promoters, Jang eventually determined
that luteolin inhibited IL-6 production by preventing activator
protein-1 (AP-1) from binding the IL-6 promoter.

AP-1 is in turn activated by JNK, an upstream protein kinase. Jang
found that luteolin inhibited JNK phosphorylation in microglial cell
culture. The failure of the JNK to activate the AP-1 transcription
factor prevented it from binding to the promoter region on the IL-6
gene and transcription came to a halt.

To see if luteolin might have a similar effect in vivo, the
researchers gave mice luteolin-laced drinking water for 21 days before
injecting the mice with LPS.

Those mice that were fed luteolin had significantly lower levels of
IL-6 in their blood plasma four hours after injection with the LPS.
Luteolin also decreased LPS-induced transcription of IL-6 in the
hippocampus, a brain region that is critical to spatial learning and
memory.

The findings indicate a possible role for luteolin or other bioactive
compounds in treating neuroinflammation, Johnson said.

"It might be possible to use flavonoids to inhibit JNK and mitigate
inflammatory reactions in the brain," he said. "Inflammatory cytokines
such as interleukin-6 are very well known to inhibit certain types of
learning and memory that are under the control of the hippocampus, and
the hippocampus is also very vulnerable to the insults of aging," he
said. "If you had the potential to decrease the production of
inflammatory cytokines in the brain you could potentially limit the
cognitive deficits that result."

----------------------------
Article adapted by Medical News Today from original press release.
Source: Diana Yates
University of Illinois at Urbana-Champaign
----------------------------

http://www.eurekalert.org/pub_releases/2007-08/apa-nrs080807.php

New research shows how chronic stress worsens neurodegenerative
disease course
Interventions can prevent or halt stress-related inflammation that
aggravate neurodegenerative disease, study shows

SAN FRANCISCO - The evidence is accumulating on how bad stress is for
health.
Chronic stress can intensify inflammation and increase a
person's risk for developing central nervous system infections,
neurodegenerative diseases, like multiple sclerosis (MS), and other
inflammatory diseases, say researchers presenting at the 115th Annual
Convention of the American Psychological Association (APA).
These researchers have demonstrated for the first time that stress-
related increases in central nervous system inflammation are behind
the adverse effects of stress in an animal model of MS.

Researchers from Texas A & M University used mice to show what role
social stress plays in the immune process to influence the course of
an MS-like disease.
They proposed that stress-induced increases of pro- inflammatory
cytokines, which are proteins that regulate immune and
inflammatory functions, inhibit the clearing of a virus and allow the
inflammatory process to run amok.
Stress, say the authors, may interact with viral infections to
increase vulnerability to diseases such as MS.
Meta-analysis of studies investigating the impact of
stressful events in patients with MS show an increased risk of
worsening symptoms of the disease.

In a series of experiments on mice, the authors showed that increases
in a particular cytokine - interleukin-6 (IL-6), which is released
during stress and regulates the part of the immune system that fights
infection - can make socially stressed mice vulnerable to MS-like
illnesses.

The researchers used a social disruption model (SDR) to simulate
social stress for mice and then infected the mice with Theiler's
murine encephalomyelitis (TMEV). Infection with TMEV results in an
acute infection of the central nervous system followed by a chronic
autoimmune disease similar to that seen in humans with MS.
Their laboratory has previously shown that exposure to social stress
prior to infection exacerbates both the early viral infection and the
later autoimmune demyelinating MS-like phase of the disease.

To create a stressful environment, researchers housed three young male
mice together for several weeks.
After the mice established a stable social hierarchy, researchers
introduced an older aggressive male into the residence for a couple of
hours.
The intruder exhibits aggressive behavior - posturing, fighting,
wounding, pursuit - that results in submissive behaviors and social
defeat in the younger resident mice.
This procedure was repeated for three consecutive nightly two-hour
sessions with one night off, followed by an additional three nightly
sessions.
To keep the mice from getting used to the intruder, a new intruder was
introduced for each session.

What they found was this stress appears to elevate levels of IL-6,
which subsequently increases the severity of the MS-like illness.
Furthermore, using specific IL-6 neutralizing antibody treatments
during the stress exposure can prevent the stress-related worsening of
the disease, said the authors.

In one experiment, they showed that mice exposed to social disruption
had elevated central and peripheral levels of IL-6. However, infusing
the neutralizing antibody into the brain prevented this stress-induced
increase in IL-6.
This demonstrated that the antibody could effectively reverse the
stress-related increases in IL-6 in brain and in circulating blood.
----------------------------

Molecule May Drive Multiple Sclerosis-Linked Disorder
Discovery could lead to treatments for transverse myelitis and MS

WEDNESDAY, Oct. 12 (HealthDay News) -- Researchers report that a
single molecule called IL-6 is the cause of transverse myelitis (TM),
an autoimmune disease in the central nervous system that's related to
multiple sclerosis.

The study found that levels of IL-6 are dramatically elevated in the
spinal fluid of people with TM. The finding may help in the
development of treatments for both TM and multiple sclerosis.

This is the first time a single culprit has been identified as
causing
a CNS (central nervous system) autoimmune disease," researcher Dr.
Adam Kaplin, a psychiatrist and assistant professor of medicine at
Johns Hopkins University School of Medicine, said in a prepared
statement.

IL-6 is a chemical messenger that immune system cells use to
communicate with each other. Most TM patients suffer a single attack,
but 15 percent to 30 percent of TM patients go on to develop full-
blown multiple sclerosis. TM usually results in permanent impairment,
including leg and arm weakness, bowel and bladder dysfunction, pain
and paralysis.

The researchers decided to investigate IL-6 because TM patients suffer
from memory impairment and depression. Previous research implicated
IL-6 in mood and concentration disorders.

The study appears in the October issue of the Journal of Clinical
Investigation.

The U.S. National Institute of Neurological Disorders and Stroke has
more about transverse myelitis.

-- Robert Preidt

SOURCE: Johns Hopkins Medicine, news release, news release, Sept. 22,
2005

Last Updated: Oct. 12, 2005

Copyright © 2005 ScoutNews LLC. All rights reserved

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<<snip>>
IL6-induced BBB defect precipitates iron accumulation
<<snip>>

J Neuropathol Exp Neurol. 1998 Mar;57(3):268-82. Related Articles,
Links

Abnormal iron deposition associated with lipid peroxidation in
transgenic mice expressing interleukin-6 in the brain.

Castelnau PA, Garrett RS, Palinski W, Witztum JL, Campbell IL, Powell
HC.

Department of Pathology (Neuropathology), School of Medicine,
University of California San Diego and the Veterans Affairs Research
Service, La Jolla 92093-0612, USA.

Transgenic mice, named GFAP-IL6, that express interleukin-6 in
astrocytes in the central nervous system (CNS) have a constitutive
blood-brain barrier (BBB) defect and develop a progressive
neurodegenerative disease.
Based on ultrastructural observations showing electron-dense pigment
in the brain of the GFAP-IL6 mice, we hypothesized that iron
metabolism was altered in the brains of these animals.
Enhanced histochemical methods revealed abnormal iron
deposition in the cerebellum from 1 month of age that worsened with
progression of the disease.
Immunohistochemical analysis of iron-binding proteins (IBP) showed
increased ferritin immunoreactivity and a decreased signal from the
transferrin receptor in symptomatic animals.
Atomic absorption spectroscopy revealed a 40% increase of
total iron concentration in the cerebellum at the symptomatic stage.
In order to obtain evidence that accumulation of this oxidizing metal
was toxic, we looked for the presence of oxidative damage. Using the
MAL-2 antibody, extensive lipid peroxidation (LP) was detected in the
neocortex and the cerebellum in symptomatic animals.
Ultrastructural analysis indicated lipofuscin deposition at the sites
of neuro-axonal degeneration and abnormal iron deposition.
These results suggest that the IL6-induced BBB defect precipitates
iron accumulation in the GFAP-IL6 mouse brain and that subsequent IBP
regulation mediates protective responses.
As these defenses become overwhelmed, the iron overload seems to
promote LP, which may contribute to the neurodegeneration that
ensues.
This transgenic mouse model of IL6-mediated neurodegeneration provides
a unique opportunity to examine several aspects of iron metabolism in
the brain, including its entry at the site of the BBB, its
distribution through the IBP, and its mechanisms of toxicity.

PMID: 9600219 [PubMed - indexed for MEDLINE]

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