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Molecular neurobiology
May, 2021;58 (5): 2158-2182.

Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry.

G Morris, A J Walker, K Walder, M Berk, W Marx, A F Carvalho, M Maes, B K Puri
Author Information
  1. G Morris: Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.
  2. A J Walker: Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.
  3. K Walder: Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.
  4. M Berk: Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.
  5. W Marx: Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.
  6. A F Carvalho: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
  7. M Maes: Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.
  8. B K Puri: C.A.R., Cambridge, UK. bpuri@cantab.com. ORCID
PMID: 33411248 DOI: 10.1007/s12035-020-02212-w

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.

Keywords

Coenzyme Q10 Melatonin Molecular neurobiology N-acetylcysteine Nrf2 Oxidative stress

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MeSH Term

Animals
Brain
Humans
Mental Disorders
Mitochondria
NF-E2-Related Factor 2
Neuropsychiatry

Chemicals

NF-E2-Related Factor 2
NFE2L2 protein, human
Journal Article Review

Word Cloud

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