Sulforaphane as a potential nutritional intervention to reduce neuroinflammation associated with aging and sickness behavior

Townsend, Brigitte Elyse

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Description

Title

Sulforaphane as a potential nutritional intervention to reduce neuroinflammation associated with aging and sickness behavior

Author(s)

Townsend, Brigitte Elyse

Issue Date

2015-04-22

Director of Research (if dissertation) or Advisor (if thesis)

Johnson, Rodney W.

Doctoral Committee Chair(s)

Jeffery, Elizabeth H.

Committee Member(s)

• Erdman, John W.
• Dilger, Ryan N.

Department of Study

Nutritional Sciences

Discipline

Nutritional Sciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Aging
• Broccoli
• Neuroinflammation
• Sickness Behavior
• Sulforaphane

Abstract

Innate immune cells provide critical protection against pathogens and produce immune factors that drive adaptive sickness behaviors to facilitate recovery from acute illness and injury. Microglia, the resident innate immune cells in brain, recognize pathogens and danger associated molecular patterns, then express proinflammatory signaling molecules such as interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase (iNOS). Aging is associated with chronic neuroinflammation that is represented by behavioral and cognitive impairment, and increased risk of neurodegenerative disease. Aging-associated inflammation is thought to shift microglia into a primed state that contributes to increased neuroinflammation and oxidative stress in the aging brain. Dietary broccoli and its derived bioactive sulforaphane (SFN) has potential use as a novel nutritional intervention to reduce aging-related neuroinflammation. Sulforaphane activates nuclear factor E2-related factor 2 (Nrf2), which induces antioxidant response element genes that regulate cellular redox balance. In animal models of neurodegeneration and brain trauma, activation of the Nrf2 pathway is protective, but its function in the aging brain has not been investigated. Microglial activity is reportedly mitigated by SFN, forming the basis for our hypothesis that SFN would attenuate elevated inflammatory markers in unstimulated aged microglia and in microglia treated with lipopolysaccharide (LPS). To test this hypothesis, microglia from adult and aged mice were isolated and treated in vitro with SFN ± LPS in order to investigate the effects of SFN on aged and LPS-stimulated microglia. In support of the hypothesis, SFN decreased IL-1β, IL-6, and iNOS in LPS-simulated microglia from adult and aged mice, and tended to decrease basal IL-1β in aged microglia. Sulforaphane increased Nrf2 target genes were increased in both adult and aged microglia, and increased Nrf2 activity in the BV2 microglia cell line. Based on SFN’s ability to reduce inflammatory markers in microglia, we hypothesized that acute exposure to SFN may attenuate neuroinflammation and sickness behavior in LPS-challenged mice. Mice were administered SFN for 3 d then challenged with LPS to mimic peripheral infection. Nrf2 target genes and inflammatory mediators in brain and liver mRNA were quantified after 6 h. In hippocampus and liver of mice that were treated with LPS, SFN decreased IL-1β and iNOS, but did not improve sickness behavior. This led us to hypothesize that longer exposure to SFN, such as could be attained through dietary supplement with broccoli, may have a more pronounced impact on sickness behavior. To test this hypothesis, adult and aged mice were fed control diet or diet containing 10% broccoli. After 28 d, mice were injected with saline or LPS, and sacrificed 24 h later. Broccoli diet improved glial reactivity markers in aged mice. However, broccoli diet did not reduce IL-1β in brain or liver of aged or LPS-challenged mice, and had no effect on sickness behavior. Collectively these data provide novel evidence that SFN supplementation and dietary broccoli may be a beneficial nutritional intervention to reduce inflammation that is associated with aging and with peripheral infection.

Graduation Semester

2015-5

Type of Resource

text

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Copyright and License Information

Copyright 2015 Brigitte E. Townsend

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