Brain studies yield cytokine surprises

[Guest guest]

Thought you might be interested in this study since TNF-a is one of the

cytokines elevated in some of the children. Here is validation that it

reduces brain bloodflow.

Cheryl

Source: http://news.bmn.com/news/story?day=020718 & story=1

Brain studies yield cytokine surprises

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16 July 2002 15:00 GMT

by Bea Perks, BioMedNet News

[MRI] Paris - Tumor necrosis factor alpha (TNF-alpha) is known

to widen blood vessels and increase blood flow in the peripheral

nervous system. But Oxford-based scientist Nicola Sibson has

now shown that this vasodilatory effect is reversed in the central

nervous system, where TNF-alpha is vasoconstrictive, a

surprising finding that could lead to novel therapeutic

possibilities for a range of disorders.

Although TNF-alpha has been associated with a broad spectrum

of neuropathologies, from multiple sclerosis to cerebral malaria,

its actions beyond the periphery have been little understood.

Sibson, a research fellow at the MRC Biochemical and Clinical

Magnetic Resonance Unit in Oxford who used magnetic

resonance imaging (MRI) to measure the effect of this cytokine

in the brain, presented her data here today at the third biennial

forum of the Federation of European Neuroscience Societies.

Sibson injected rats intracerebrally with a solution containing rat

recombinant TNF-alpha, and the brains of the (live) animals

were then analyzed by MRI. Bright patches on the MR image

indicated areas of high cerebral blood volume, while darker

patches signified lower blood volume. Comparisons were made

between injected striatum, a type of connective brain tissue, and

non-injected striatum in each individual brain.

" As early as one hour after injection we could see a reduction in

blood volume in injected striatum compared with non-injected

striatum, " said Sibson. " This is really quite a striking and

unexpected effect. Most studies have shown that, in the

periphery, TNF-alpha actually causes vasodilation. "

TNF-alpha has two cellular receptors, TNFR1 and TNFR2, so

Sibson set out to find out which of them was responsible for the

effect of TNF-alpha on cerebral blood volume. She made use of

the fact that human recombinant TNF-alpha, unlike its rat

recombinant homolog, only binds to rat TNFR1. She injected

rats with the human recombinant cytokine and found that there

was no change in cerebral blood volume. Thus, she concludes,

the vasoconstrictive effect of TNF-alpha in the brain is mediated

by the TNFR2 receptor.

She notes that in peripheral tissue, by contrast, the TNFR2

receptor is generally associated with the inflammatory effects of

TNF-alpha.

Sibson's findings join a growing body of data revealing that the

well-described peripheral effects of cytokines cannot be

extrapolated to the central nervous system. " [These reported

effects] couldn't be predicted from experiments either in tissue

culture or examining the systemic organs, " said ,

lecturer in experimental neuropathology at the University of

Southampton, who chaired this morning's session on The

unusual behavior of proinflammatory mediators in the CNS. " In

the brain you induce different pathways and you get different

physiological effects. "

Many cytokine networks that exist in the periphery are now being

found not to exist in the CNS and vice versa, he says.

" There's an awful lot of noise in the literature, " said. " A

lot of that noise has come from the fact that people can put an

inflammatory mediator onto a neuron, or onto an astrocyte [a

type of CNS cell], and they will do something completely different

from what they do in the central nervous system. " Nevertheless,

he adds, data from in vitro studies are often extrapolated,

inappropriately, to predict effects in the CNS.

Differences in cytokine networks between the CNS and

periphery could, however, provide researchers with new

avenues for treating CNS disorders, says .

" The CNS may be lending itself to better therapeutic intervention

because it induces discrete pathways, " he said. " There is the

possibility you [could] inhibit individual pathways in the CNS that

wouldn't be possible in the periphery ... A drug that didn't work in

the periphery may work in the CNS. "

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