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Drug Development and Discovery
Excessive innate immune (inflammatory) responses may be an important contributor to the development of major depression (MD). Increased inflammatory immune responses have been found in patients with MD, and patients treated with innate immune cytokines for viral infections or cancer often develop key diagnostic features of MD. As such, a novel treatment approach for MD is to block excessive innate immune activation. The studies proposed herein will examine the effectiveness of novel anti-inflammatory compounds to block inflammation-induced depressive-like behaviors in mice. Mice will be treated with the bacterial endotoxin, lipopolysaccharide (LPS), which induces robust inflammatory immune activity in the brain as well as depressive-like behaviors (e.g., reduced preference for sweetened water and decreased social interaction). Compounds that specifically target relevant inflammatory signaling pathways including p38 mitogen activated protein kinase (MAPK) and nuclear factor-kB (NF-kB), a lynchpin in the inflammatory signaling cascade, will be used. We hypothesize that blocking p38 MAPK and/or NF-kB will prevent LPS-induced brain inflammatory responses and behavioral changes in mice. |
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