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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.

Type

Journal article

Journal

Brain

Publication Date

11/2002

Volume

125

Pages

2446 - 2459

Keywords

Animals, Antigens, CD, Blood-Brain Barrier, Brain, Central Nervous System Diseases, Cerebrospinal Fluid, Cerebrovascular Circulation, Drug Administration Schedule, Endothelins, Energy Metabolism, Homeostasis, Magnetic Resonance Imaging, Male, Neostriatum, Rats, Rats, Wistar, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type II, Recombinant Fusion Proteins, Signal Transduction, Tumor Necrosis Factor-alpha, Water-Electrolyte Balance