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

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.