. 2018 Nov 28;21:101059. doi: 10.1016/j.redox.2018.11.017

Table 1.

NRF2 enhancers for the treatment of oxidative stress-promoted cerebrovascular and neurodegenerative disorders.

NRF2 enhancers	Category	The role in antioxidative systems	Ref.
Sulforaphane	Organic isothiocyanate	• Activates the NRF2-KEAP1 pathway through direct modifications of KEAP1 cysteines.	[8], [19], [160], [172], [180], [181], [182], [183], [184], [185], [186], [187], [188], [189], [190]
Sulforaphane	Organic isothiocyanate	• Promotes the ribosomal internalization of NRF2 mRNA for protein synthesis.
Metformin	Biguanide	• Activates of AMPK related pathways	[75], [77], [194], [195], [196], [197]
		• Activates the NRF2-ARE signaling pathways reducing oxidative stress, inflammation, and loss of BBB integrity
		• Promotes the neurogenesis and spatial memory formation
		• Attenuates BBB disruption and reduces post- ischemic brain injury
Astragaloside IV	Bioactive saponin	• Inhibits ROS generation and activating the NRF2-ARE pathway in neuronal cells	[222], [223]
		• Protects the BBB integrity from LPS-induced disruption by activating the NRF2-ARE pathway
		• Anti-inflammatory activities on BBB endothelial cells
		• Decreases the adhesion of murine dendritic cells JAWS II onto bEnd.3 cells
Curcumin	Polyphenol	• Activates the NRF2-ARE signaling pathways leading to attenuating brain injury in the TBI	[106], [205], [206], [207], [208], [209], [210], [224]
		• Increases the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase
		• Antioxidant, anti-inflammatory and anti-infective properties
EGCG	Polyphenol	• Up-regulates of NRF2/HO-1 via activation of the p38 MAPK and ERK1/2 signaling pathways	[214], [215], [216]
EGCG	Polyphenol	• Promotes the dissociation of NRF2 from KEAP1 and its nuclear translocation	[214], [215], [216]
Genistein	Isoflavone	• Up-regulates NRF2/HO-1 via KEAP1 S-nitrosylation	[225], [226]
Genistein	Isoflavone	• Activates the NRF2-ARE signaling pathway via modulation of PI3K activity in cerebrovascular endothelial cells	[225], [226]
Fisetin	Flavonoid	• Activates of the NRF2– ARE signaling pathway	[227]
Fisetin	Flavonoid	• Includes anti-carcinogenic, anti-inflammatory, anti-viral, and immune-stimulatory activity properties.	[227]
Melatonin	Hormone	• Enhances expression and activity of antioxidant enzymes	[194], [228], [229], [230], [231], [232], [233], [234]
Melatonin	Hormone	• Attenuates brain injury in TBI, potentially through activation of the NRF2–ARE signaling pathway.	[194], [228], [229], [230], [231], [232], [233], [234]