TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway
Sibson, N.R., Blamire, A.M., Perry, V.H., Gauldie, J., Styles, P. and Anthony, D.C. (2002) TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway. Brain, 125, (11), 2446-2459.
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Description/Abstract
TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies.
| Item Type: | Article |
|---|---|
| ISSNs: | 0006-8950 (print) |
| Related URLs: | |
| Subjects: | Q Science > QH Natural history > QH301 Biology |
| Divisions: | University Structure - Pre August 2011 > School of Biological Sciences |
| Item ID: | 56074 |
| Date Deposited: | 07 Aug 2008 |
| Last Modified: | 12 May 2013 01:10 |
| Contributors: | Sibson, N.R. (Author) Blamire, A.M. (Author) Perry, V.H. (Author) Gauldie, J. (Author) Styles, P. (Author) Anthony, D.C. (Author) |
| Date: | 1 November 2002 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/56074 |
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