TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.

Journal article

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.

Authors: Sibson, N; Blamire, A; Perry, V; Gauldie, J; Styles, P

• Publication status: Published
• Journal: Brain : a journal of neurology
• Volume: 125
• Issue: Pt 11
• Pages: 2446-2459
• Publication date: 2002-11-01
• DOI: 10.1093/brain/awf256
• EISSN: 1460-2156
• ISSN: 0006-8950
• Language: English
• Keywords: Endothelins; Blood-Brain Barrier; Central Nervous System Diseases; Antigens, CD; Brain; Homeostasis; Energy Metabolism; Rats; Water-Electrolyte Balance; Cerebrospinal Fluid; Rats, Wistar; Magnetic Resonance Imaging; Signal Transduction; Receptors, Tumor Necrosis Factor, Type II; Neostriatum; Tumor Necrosis Factor-alpha; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Drug Administration Schedule; Cerebrovascular Circulation; Animals; Male