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The Role of Nrf2 in Neuroinflammation and the Impact of Botanicals
Author(s) -
Krepel Stacey A,
Hogan Mary B,
Mangum Sally,
Kuhn Thomas B
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.16
Subject(s) - keap1 , oxidative stress , proinflammatory cytokine , neuroinflammation , microbiology and biotechnology , tumor necrosis factor alpha , cytosol , chromosomal translocation , chemistry , transcription factor , neurodegeneration , biology , endocrinology , inflammation , medicine , biochemistry , immunology , disease , gene , enzyme
Persistent inflammatory and oxidative stress is largely responsible for the progressive loss of neuronal integrity and connectivity underlying the continuous decline of cognitive function associated with most chronic CNS disorders as well as normal aging. The transcription factor Nrf2, a master redox regulator, plays a pivotal role in the antioxidant defense of non neuronal and neuronal cells. Nrf2 remains sequestered in the cytosol of cells under basal conditions tightly bound to its repressor Keap1 and upon oxidative stress dissociates from Keap1 and translocates into the nucleus to stimulate transcription of antioxidant defense mechanisms. It is not clear how duration and extent of oxidative stress impact activation and nuclear translocation of Nrf2 in neuronal cells. Exposure of SH‐SY5Y human neuroblastoma cells to peroxide (250 μM H 2 O 2 , 1 h) considerably increased the presence of Nrf2 in the nuclear fraction indicative of translocation of Nrf2 from the cytosolic to the nuclear compartment. Immunocytochemistry against Nrf2 corroborated this finding. Exposure of SH‐SY5Y neuroblastoma cells (1 h) to the proinflammatory cytokine TNFa at concentrations ranging from 50 ng/ml to 400 ng/ml triggered the translocation of Nrf2 into the nucleus where as prolonged exposure (4 h) to TNFa (200 ng/ml) revealed significantly stronger presence of Nrf2 in the nuclear compartment. However, prolonged exposure of SH‐SY5Y cells to TNFa (24 h) at concentrations of 200 ng/ml or higher also resulted in significant cell death due to oxidative stress. Together these findings suggest that, in response to TNFa stress, Nrf2‐enhanced antioxidant defenses were insufficient. One of the many health benefits of nutrition rests on the capacity of distinct botanicals to directly act on biochemical mechanisms rather than through passive antioxidant capacities. Several botanicals including some polyphenols have the potency to stimulate Nrf2 activity and thus increase antioxidant defense mechanisms. We demonstrated that supplementation of SH‐SY5Y neuroblastoma cells with crude extracts or non polar extracts (5 μg/ml each) obtained from Alaska wild bog blueberries significantly increased neuronal viability in the prolonged presence of 200 ng/ml TNFa. Incubation of SH‐SY5Y cells with distinct blueberry extracts alone stimulated Nrf2 activation, which could at least partially explain the reported neuroprotective potency of diets rich in berry fruits. Understanding the regulation of Nrf2 through botanicals could provide vital insight for developing neuroprotective strategies applicable to an array of neurodegenerative diseases. Support or Funding Information Supported in part by NIH grants RL56M118990, 1UL16M18991, TL4GM118992, and generous donations from the Alzheimer'r Resources of Alaska. The work is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health