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The GSK3-NRF2 Axis in Suicide

Gänsbühlgartenweg 7, CH-4132 Muttenz, Switzerland
Retired Pharmacologist.
Received: 15 February 2021 / Revised: 2 March 2021 / Accepted: 19 March 2021 / Published: 21 March 2021
Mutations in the genes coding for tryptophan-hydrolase-2 and the scaffold protein FKBP5 are associated with an increased risk of suicide. The mutation in both cases enhances the enzymatic activity of glycogen synthase kinase-3 (GSK3). Conversely, anti-suicidal medications, such as lithium, clozapine, and ketamine, indirectly inhibit the activity of GSK3. When GSK3 is active, it promotes the metabolic removal of the transcription factor NRF2 (nuclear factor erythroid 2-related factor-2), which suppresses the transcription of multiple genes that encode anti-oxidative and anti-inflammatory proteins. Notably, several suicide-biomarkers bear witness to an ongoing inflammatory process. Moreover, alterations in serum lipid levels measured in suicidal individuals are mirrored by data obtained in mice with genetic deletion of the NRF2 gene. Inflammation is presumably causally related to both dysphoria and anger, two factors relevant for suicide ideation and attempt. Preventing the catabolism of NRF2 could be a strategy to obtain novel suicide-prophylactic medications. Possible candidates are minocycline and nicotinic-α7 agonists. The antibiotic minocycline indirectly activates NRF2-transcriptional activity, whereas the activation of nicotinic-α7 receptors indirectly inhibits GSK3. View Full-Text
Keywords: suicide pathophysiology; GSK3; NRF2; ketamine; minocycline; nicotinic-α7 receptor; clozapine; biomarker; lipid profile suicide pathophysiology; GSK3; NRF2; ketamine; minocycline; nicotinic-α7 receptor; clozapine; biomarker; lipid profile
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MDPI and ACS Style

Kalkman, H.O. The GSK3-NRF2 Axis in Suicide. Psychiatry Int. 2021, 2, 108-119. https://0-doi-org.brum.beds.ac.uk/10.3390/psychiatryint2010008

AMA Style

Kalkman HO. The GSK3-NRF2 Axis in Suicide. Psychiatry International. 2021; 2(1):108-119. https://0-doi-org.brum.beds.ac.uk/10.3390/psychiatryint2010008

Chicago/Turabian Style

Kalkman, Hans O. 2021. "The GSK3-NRF2 Axis in Suicide" Psychiatry International 2, no. 1: 108-119. https://0-doi-org.brum.beds.ac.uk/10.3390/psychiatryint2010008

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