Brain, Vol. 125, No. 11, 2446-2459,
November 2002
© 2002 Oxford University Press
TNF-
reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway
1 MRC Biochemical and Clinical Magnetic Resonance Unit, Department of Biochemistry, University of Oxford, Oxford, 2 CNS Inflammation Group, 3 Molecular Neuropathology Laboratory, School of Biological Sciences, University of Southampton, Southampton, UK, 4 Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada
Correspondence to: N. R. Sibson, MRC Biochemical and Clinical Magnetic Resonance Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK E-mail: niki{at}bioch.ox.ac.uk
TNF-
expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF- expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF- causes a significant, acute reduction (15–30%) in cerebral blood volume (CBV), which is dependent on TNF--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- injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-, achieved through the use of an adenoviral vector expressing TNF- cDNA (Ad5TNF-m), caused a sustained depression in CBV in accordance with the single TNF- bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF- within the brain, and suggest that antagonists of the endothelin and TNF- type 2 receptors may be therapeutic in TNF--associated neuropathologies.
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