Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases.

Circulating cytokine levels are elevated in many neuropathologies and may be a cause of the associated malaise and depression. Using a rat model, we demonstrate that sickness behaviors generated by microinjection of IL-1beta into the anterior hypothalamus are adopted by naive recipient animals following plasma transfer. We further show that neutralizing peripheral TNF by etanercept (a p75 TNF receptor/Fc fusion protein) prior to the IL-1beta microinjection inhibits certain IL-1beta-mediated sickness behaviors, such as the depression of open-field activity and reduced glucose consumption. IL-1beta-induced central lesions induce peripheral TNF as part of the acute-phase response, and this appears to be the principal target of the etanercept. Thus behavioral changes induced by CNS lesions may result from peripheral expression of cytokines that can be targeted with drugs which do not need to cross the blood-brain barrier to be efficacious.