NRF2 Activation and Downstream Effects: Focus on Parkinson’s Disease and Brain Angiotensin

Abstract

Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson’s disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson’s disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches.

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells

“…Upregulation of peroxiredoxins 3 and 5 by quercetin in an in vitro model of trabecular meshwork was shown to be dependent on the NRF2/NRF1 pathway, which protects against ocular-disease-induced oxidative stress [ 121 ]. NRF2 showed a neuroprotective response upon angiotensin-II-induced oxidative stress in neurons in a model of Parkinson’s disease, both in vivo and in vitro [ 122 ]. MitoQ, a mitochondria-targeted antioxidant, protected intestinal epithelial cells (IECs) from mtDNA damage induced by ischemia/reperfusion (I/R) through the activation of the NRF2 signaling pathway [ 123 ].…”

Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions

“…As previously mentioned, among different signaling pathways activated by oxidative stress and neuroinflammation, of particular importance are those mediated by NF-κB, which directs the synthesis of proinflammatory cytokines and induces the expression of iNOS and COX-2, and by nuclear factor-erythroid-2-like 2 (Nrf2), which regulates the expression of antioxidant mediators such as SOD1, heme oxygenase-1 (HO-1), catalase, and glutathione S-transferase. Following nuclear translocation, Nrf2 interacts with antioxidant response element (ARE) and orchestrates a neuronal response to oxidative injury by driving the transcription of antioxidant genes [ 157 , 177 ]…”

“…The effects of cannabinoids on NF-κB and Nrf2 signaling should be further investigated as targeting these pathways has been considered an important neuroprotective strategy with relevant therapeutic implications [ 177 , 178 , 179 ]. A putative ARE motif was found in the CNR2 receptor gene and displays a high similarity with the consensus ARE sequence.…”

Role of Nrf2 in Parkinson’s Disease: Toward New Perspectives

“…In addition, the main proteins regulated by Nrf2 are HO-1, nicotinamide adenine dinucleotide phosphate quinone reductase-1 (NQO-1), glutamate cysteine ligase, GSH, GPx, and several phase I and II enzymes (Jayaram & Krishnamurthy, 2021;Parga et al, 2021). These enzymes are closely associated with the production and consumption of ROS.…”