The proposed research is designed to test the effects of UBS109, a nuclear factor-kappa B (NF-kB) inhibitor, on behavioral alterations in a mouse model of cytokine-induced depressive-like behavior. Mounting data suggest that pro-inflammatory cytokines may play a role in the development of depression in humans, especially in individuals who are non-responsive to conventional antidepressant strategies. Recent findings suggest that NF-kB, which is a lynchpin in the inflammatory response, may play a key role in transmitting cytokine signals from the periphery to the brain, ultimately contributing to the release of pro-inflammatory cytokines within the CNS. These cytokines, in turn, have been shown to induce depressive-like behaviors in laboratory animals and humans. Thus, NF-kB represents an attractive therapeutic target for the development of drugs that can prevent cytokine-induced behavioral changes. Work in the sponsor's laboratory is focused on the development of anologues of curcumin, a component of the Indian spice, turmeric, which improve upon curcumin's anti-NF-kB activity as well as its bioavailability. One such analogue is UBS109, which exhibits ~100 fold greater inhibition of NF-kB activity than curcumin. Furthermore, the applicant's preliminary data shows that oral administration of UBS109 to mice leads to reduced expression of proinflammatory cytokines in the brain in response to lipopolysaccharide (IPS). Nevertheless, the extent to which UBS109 alters LPS-induced behavioral changes is unknown. Based on the applicant's preliminary data, it is hypothesized that UBS109 will reduce LPS-induced NF-kB activity, which will in turn lead to a reduction in CNS cytokine expression and behavioral alterations. To test this hypothesis, the applicant will examine the capacity of UBS109 to reduce LPS-induced NF-kB activity and NF-kB dependant cytokine gene and protein expression using NF-kB-DNA binding ELISA and RT-PCR in adult male C57/BL6 mice. In addition, the effects of UBS109 on LPS-induced behavioral changes (e.g. decreased locomotor activity and increased immobility in the forced swim test) will be determined. DNA microarray and the TELiS database will be used to identify other possible inflammatory pathways that may be modulated by UBS109 treatment. Finally, given evidence that antagonism of inflammatory signaling pathways can lead to an antidepressant phenotype, the behavioral effects of UBS109 will be examined in the absence of LPS. The goal of the proposed research is to develop novel drugs that target inflammatory signaling pathways and thereby lead to alternative approaches for treating patients with depression, especially those who are unresponsive to or intolerant of conventional antidepressant medications.
|Olivera, Anlys; Moore, Terry W; Hu, Fang et al. (2012) Inhibition of the NF-?B signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol 12:368-77|