title: TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway.
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.
authors.affiliation: MRC Biochemical and Clinical Magnetic Resonance Unit, Department of Biochemistry, University of Oxford, UK. niki@bioch.ox.ac.uk
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blamire
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Peter
authors.initials: P
authors.lastname: Styles
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002555:Cerebrospinal Fluid / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004334:Drug Administration Schedule; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology
chemical_list: D015703:Antigens, CD; D016232:Endothelins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha