Targeting the Nrf2 signaling pathway using phytochemical ingredients: A novel therapeutic road map to combat neurodegenerative diseases

Background: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a classical nuclear transcription factor that reg-ulates the system's anti-oxidative stress response. The activation of Nrf2 induces the expression of antioxidant proteins and improves the system's anti-oxidative stress ability. Accumulating evidence suggests that Nrf2-centered signaling pathways may be a key pharmacological target for the treatment of neurodegenerative dis-eases (NDDs). However, phytochemicals as new therapeutic agents against NDDs have not been clearly delineated. Purpose: To review the therapeutic effects of phytochemical ingredients on NDDs by activating Nrf2 and reducing oxidative stress injury. Methods: A comprehensive search of published articles was performed using various literature databases including PubMed, Google Scholar, and China National Knowledge Infrastructure. The search terms included "Nrf2", "phytochemical ingredients", "natural bioactive agents", "neurodegenerative diseases", "Antioxidant", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", "amyotrophic lateral sclerosis" "multiple sclerosis", "toxicity", and combinations of these keywords. A total of 769 preclinical studies were retrieved until August 2022, and we included 39 of these articless on phytochemistry, pharmacology, toxicology and other fields. Results: Numerous in vivo and in vitro studies showed that phytochemical ingredients could act as an Nrf2 acti-vator in the treatment of NDDs through the antioxidant defense mechanism. These phytochemical ingredients, such as salidroside, naringenin, resveratrol, sesaminol, ellagic acid, ginsenoside Re, tanshinone I, sulforaphane, curcumin, naringin, tetramethylpyrazine, withametelin, magnolol, piperine, and myricetin, had the potential to improve Nrf2 signaling, thereby combatting NDDs. Conclusion: As Nrf2 activators, phytochemical ingredients may provide a novel potential strategy for the treatment of NDDs. Here, we reviewed the interaction between phytochemical ingredients, Nrf2, and its antioxidant damaging pathway in NDDs and explored the advantages of phytochemical ingredients in anti-oxidative stress, which provides a reliable basis for improving the treatment of NDDs. However, further clinical trials are needed to determine the safety and efficacy of Nrf2 activators for NDDs.