The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in mitochondrial function and biogenesis. Moreover, NRF2 has been shown to directly regulate the expression of anti-inflammatory mediators reducing the expression of pro-inflammatory cytokines. In recent years, attention has turned to the role NRF2 plays in the brain in different diseases such Alzheimer's disease, Parkinson’s disease, Huntington’s disease and others. This review focused on the evidence, derived in vitro, in vivo and from clinical trials, supporting a role for NRF2 activation in maintaining and improving cognitive function and how its activation can be used to elicit neuroprotection and lead to cognitive enhancement. The review also brings a critical discussion concerning the possible prophylactic and/or therapeutic use of NRF2 activators in treating cognitive impairment-related conditions.

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

“…Resveratrol and EGCG were not considered in this review because the consequences of Nrf2 stimulation were not studied in HD animal models. However, these compounds showed cognitive enhancer activity in an animal model mediated by Nrf2 pathway stimulation [ 12 ]. Currently, DMF is the sole agent clinically available to treat neurodegenerative disease (relapsing-remitting multiple sclerosis) that acts through Nrf2 activation [ 155 ].…”

“…This review reports and discusses the scientific literature supporting the role in HD of the nuclear transcriptional factor-2 (Nrf2) that triggers an endogenous antioxidant pathway studied in different neurodegenerative disorders [ 10 , 11 , 12 , 13 ]. Moreover, a discussion on the possible prophylactic and/or therapeutic use of NRF2 activators in treating HD neurodegeneration will be presented.…”

Systems genetics identifies the association between Enc1 and cognitive function in the hippocampus

“…Healthy aging mouse models show accelerated cognitive decline in NRF2 knockout mice relative to wild-type between 6-18 months, with cognitive deficits exacerbated at older ages (17-24 months). Furthermore, cognitive performance was noted to be enhanced after treatment with NRF2 activating compounds[53]. Our PheWAS and ePheWAS of hippocampus indicated the association of Enc1 genetic polymorphisms with several cognitive traits in the CNS ( Fig.…”

“…Furthermore, cognitive performance was noted to be enhanced after treatment with NRF2 activating compounds [53]. Our PheWAS and ePheWAS of hippocampus The Enc1 knockdown leads to changes in levels of glucose, alkaline phosphatase, bilirubin, and cholesterol (Table 1).…”

NRF2 Activation by Nitrogen Heterocycles: A Review

“…Owing to their wide range of pharmacological activities, nitrogen heterocycles and analogues are essential candidate drugs for myriad of diseases, especially those in which oxidative stress and inflammation have been implicated. Interestingly, both natural and synthetic nitrogen heterocycles exert therapeutic effects in neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and many more [ 161 , 162 , 163 ]. This is due to the fact that most of these nitrogen heterocycles activate the NRF2 signaling pathway, which regulates oxidative stress and neuroinflammation, the key mediators in the development of neurodegenerative diseases.…”