Normal and Pathological NRF2 Signalling in the Central Nervous System

Abstract

The nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master regulator of antioxidant cellular response, but in the time since, numerous important biological functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases. The high oxygen consumption associated with high levels of free iron and oxidizable unsaturated lipids make the brain particularly vulnerable to oxidative stress. A good stability of NRF2 activity is thus crucial to maintain the redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, cancer, ageing, and ageing-related neurodegenerative diseases. We also discuss promising therapeutic strategies and the need for better understanding of cell-type-specific functions of NRF2 in these different fields.

Nrf2 is predominantly expressed in hippocampal neurons in a rat model of temporal lobe epilepsy

“…Nrf2 has been identified in recent years as a key transcription factor emerging as a master regulator of the cellular antioxidant response [ 51 ]. Activation of Nrf2 is protective against oxidative stress in several pathologies, including neurodegenerative and neurological disorders [ 23 ].…”

SRT1720 as an SIRT1 activator for alleviating paraquat-induced models of Parkinson's disease

“…NRF2 as a pleiotropic transcription factor has been recognized as a master regulator of antioxidant cellular response and is also involved in regulating numerous biological functions that include survival, autophagy, proteostasis, metabolism, and differentiation [ 28 ]. Since we previously found that the SIRT1-mediated NRF2 pathway [ 16 ] and NRF2 overexpression [ 89 ] can prevent PQ-induced cell injury, we next examined the involvement of NRF2 during PQ intoxication.…”

Nrf2 is predominantly expressed in hippocampal neurons in a rat model of temporal lobe epilepsy

“…Nrf2 has been identi ed in recent years as a key transcription factor emerging as a master regulator of the cellular antioxidant response (51). Activation of Nrf2 is protective against oxidative stress in several pathologies, including neurodegenerative and neurological disorders (23).…”