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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism*
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Blood-Brain Barrier / drug effects*
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Blood-Brain Barrier / physiology
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Brain / drug effects*
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Brain / metabolism
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Brain / pathology
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Central Nervous System Diseases / drug therapy
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Central Nervous System Diseases / metabolism*
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Central Nervous System Diseases / physiopathology
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Cerebrospinal Fluid / drug effects
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Cerebrospinal Fluid / metabolism
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Cerebrovascular Circulation / drug effects*
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Cerebrovascular Circulation / physiology
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Drug Administration Schedule
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Endothelins / antagonists & inhibitors
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Endothelins / metabolism*
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Energy Metabolism / drug effects
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Energy Metabolism / physiology
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Homeostasis / drug effects
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Homeostasis / physiology
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Magnetic Resonance Imaging
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Male
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Neostriatum / drug effects
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Neostriatum / metabolism
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Neostriatum / pathology
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Rats
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Rats, Wistar
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type II
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Water-Electrolyte Balance / drug effects
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Water-Electrolyte Balance / physiology
Substances
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Antigens, CD
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Endothelins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type II
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha