Alternatively, communication between the brain and the periphery could occur via leaky areas (e.g., circumventricular organs), binding to cerebral blood vessel endothelial cells, or active transport of cytokines into the brain (Maier et al., 1998; Moltz, 1993; Watkins et al., 1995). In support of this view, a peripheral injection of etanercept, which neutralizes TNFα and does not cross the BBB, is able to ameliorate sickness behavior produced by a proinflammatory manipulation (Jiang et al., 2008), and can produce antidepressant effects in patients (Krishnan et al., 2007; Tyring et al., 2006). It is possible that peripheral administration of an IL- 1R antagonist, such as Anakinra, which does not cross the BBB, may also reduce IL-1β function in the periphery and subsequently have effects on the brain. Studies are currently underway to determine if blockade or neutralization of IL-1β in the periphery is sufficient to block the effects of stress and/or produce antidepressant effects in cellular and behavioral models of depression.
