Also of interest are studies of interferon-a, used for the treatment of hepatitis or cancer, which results in depressive-like symptoms in a large number of patients. Here we discuss a few of the most interesting targets for treatment of depression; for a more thorough review see ref 167. TNFα and depression One of the most consistently altered proinflammatory cytokines in depressed subjects is TNFα. An inverse correlation between levels of TNFα and treatment response has been reported.168,169 TNFα immunotherapy also causes depression, indicating Inhibitors,research,lifescience,medical that this cytokine may contribute to the etiology of mood disorders and is not simply a marker for
depression (for reviews see refs 168,170). Moreover, a recent large clinical trial using an antibody neutralization approach demonstrated significant antidepressant effects of TNFα reduction.171 This finding is supported by preclinical studies demonstrating that TNFα infusions produce a prodepressive effect,172 and that TNFα receptor null mutant mice have an antidepressant phenotype in the forced swim Inhibitors,research,lifescience,medical and sucrose Inhibitors,research,lifescience,medical consumption tests.173
Taken together, the preclinical and clinical studies provide strong support for TNFα receptors, particularly TNFR2, as targets for the treatment of mood disorders. IL-1β, stress, and depression There is also strong evidence that the proinflammatory cytokine IL-1β plays a key role in the pathophysiology of stress and depression, and that the IL-1β signaling is a relevant target for drug development.174,175 These findings
include: i) clinical studies reporting an increase in serum levels IL-1β in MDD176-180;ii) reports that IL-ip produces Inhibitors,research,lifescience,medical stress like effects, including activation of the IIPA axis, regulation of monoamines, and behavioral responses in rodent models181; iii) evidence that IL-1β contributes to conditioned Inhibitors,research,lifescience,medical fear and depressive like behavior,182 and produces anhedonia and disrupts incentive motivation in rodent models183; iv) preclinical reports that IL-1β decreases hippocampal neurogenesis and underlies the decrease observed in response to stress184; v) our report that CUS-induced anhedonia and decreased neurogenesis produced by is blocked by pharmacological inhibition or null mutation of IL-1β receptors.184 Studies are currently underway to determine if blockade of peripheral, as well as central IL-1β signaling is sufficient to block the effects of stress and produce almost antidepressant actions. Interferon and IDO Recent studies demonstrate that one of the key factors contributing to the depressive actions of inflammation and activation of the innate immune system is the induction of a tryptophan degradative enzyme, indoleamine 2,3-dioxygenase (IDO). Chronic inflammation and infection can lead to sustained induction of interferon, which is then responsible for the Verteporfin supplier increased levels of IDO.