Inhibition of the NF-κB signaling pathway by the curcumin analogs, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) and 3,5-Bis(2-pyridinylmethylidene)-1-methyl-4-piperidone (UBS109): in-vitro and in-vivo studies. Público

Abstract

Mounting data suggest that pro-inflammatory cytokines may play a role in depression, especially in individuals who are non-responsive to conventional antidepressant strategies. Nuclear factor κ B (NF-κB), a lynchpin in the inflammatory response, plays a key role in transmitting cytokine signals to the brain and the release of central pro-inflammatory cytokines, which in turn have been shown to induce depressive-like behaviors in laboratory animals and humans. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits anti-inflammatory and anti-cancer properties. Curcumin analogues with enhanced activity on the NF-κB pathway have been developed including EF31 and UBS109 whose potency for NF-κB inhibition has yet to be determined.

The anti-inflammatory effects of these compounds on the NF-κB pathway were explored in-vitro in mouse RAW264.7 using lipopolysaccharide (LPS), a potent inflammatory stimulus. Compared to curcumin, EF31 and UBS109 exhibited significantly more potent inhibition of LPS-induced NF-κB pathway activity, including IκB kinase β activity, NF-κB DNA-binding activity, and downstream pro-inflammatory cytokine mRNA and protein. Curcumin analogues also demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages.

To examine the effects of curcumin analogs in-vivo, a model of LPS-induced immune and behavioral alterations was developed using C57BL/6 mice. Treatment with LPS induced a bi-phasic behavioral response characterized by sickness behaviors at 6 hours and depressive-like behaviors at 24 hours. Moreover, NF-κB DNA-binding activity peaked early in the spleen and brain, while expression of pro-inflammatory cytokines in the brain corresponded with the expression of sickness and depressive-like behaviors at 6 and 24 hours. Although curcumin analogs showed potent NF-κB inhibition in-vitro, neither reliably reduced LPS-induced NF-κB DNA-binding activity or cytokine mRNA expression in the periphery or brain.

Taken together, these data suggest that EF31 and UBS109 are potent inhibitors of NF-κB in-vitro, although modifications to the treatment paradigm in-vivo may be necessary to achieve inhibition of NF-κB, reduce inflammation, and consequently block LPS-induced behavioral alterations. Thus, both EF31 and UBS109 represent promising curcumin analogues for further therapeutic development.

Table of Contents

Chapter 1. Background: depression, inflammation, and the role of NF-κB (p. 1 - 33)
I. Depression symptoms, treatment, and current challenges (p. 2)
II. Inflammation and depressive symptoms (p. 6)
III. Innate immune cells, pathways, and cytokines (p. 10)
IV. Brain-immune interactions (p. 12)
V. The role of NF-κB in inflammation (p. 16)
VI. Inflammation and biological alterations in depression: a role for NF-κB (p. 18)
VII. Linking stress, inflammation, and depression: a role for NF-κB (p. 24)
VIII. Anti-inflammatory compounds and depression (p. 25)

Chapter 2. Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties (p. 34 - 74)
I. Introduction (p. 35)
II. Methods (p. 38)
III. Results (p. 43)
IV. Discussion (p. 50)
V. Limitations and future directions (p. 55)

Chapter 3. Animal model of LPS-induced depressive-like behaviors: measures of immune response and behavioral alterations (p. 75 - 120)
I. Introduction (p. 76)
II. Methods (p. 80)
III. Results (p. 85)
IV. Discussion (p. 91)
V. Limitations and future directions (p. 98)

Chapter 4. Effects of 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) and 3,5-Bis(2-pyridinylmethylidene)-1-methyl-4-piperidone (UBS109) on LPS-induced NF-κB pathway activity in male C57BL/6 mice (p. 121 - 153)
I. Introduction (p. 122)
II. Methods (p. 125)
III. Results (p. 130)
IV. Discussion (p. 135)
V. Limitations and future directions (p. 139)

Chapter 5. Conclusions, summary of findings, and other considerations (p. 154 - 164)
I. Introduction (p. 155)
II. Summary of data (p. 158)
III. Conclusions and considerations (p. 161)

References (pp. 165 - 200)

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	Depression curcumin Lipopolysaccharide Inflammation C57BL/6 mice Mouse RAW264.7 macrophages
Committee Chair / Thesis Advisor	Pace, Thaddeus, Emory University Miller, Andrew H, Emory University
Committee Members	Liotta, Dennis C, Emory University Shim, Hyunsuk, Emory University Sanchez, Mar, Emory University Owens, Michael J, Emory University

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