Essential Role of Keap1-Nrf2 Signaling in Mood Disorders: Overview and Future Perspective

Abstract

Depression is one of the most common mood disorders with a high rate of relapse. Accumulating evidence suggests that the transcription factor Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system plays a key role in inflammation which is involved in depression. Preclinical studies demonstrated that the protein expressions of Keap1 and Nrf2 in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of hippocampus in mice with depression-like phenotype were lower than control mice. In the learned helplessness paradigm, the protein levels of Keap1 and Nrf2 in the PFC and DG of hippocampus from rats with depression-like phenotype were also lower than control and resilient rats. Furthermore, rodents with depression-like phenotype have higher levels of pro-inflammatory cytokines. Interestingly, Nrf2 knock-out (KO) mice exhibit depression-like phenotype, and higher serum levels of pro-inflammatory cytokines compared with wild-type mice. Furthermore, Nrf2 KO mice have lower expression of brain-derived neurotrophic factor (BDNF) in the PFC, and CA3 and DG of hippocampus compared to wild-type mice. 7,8-Dihydroxyflavone, a TrkB agonist, showed antidepressant effects in Nrf2 KO mice, by stimulating BDNF-TrkB in the PFC, CA3, and DG. Pretreatment with sulforaphane, a naturally occurring Nrf2 activator, prevented depression-like phenotype in mice after inflammation, or chronic social defeat stress. Interestingly, dietary intake of 0.1% glucoraphanin (a precursor of sulforaphane) containing food during juvenile and adolescent stages of mice could prevent depression-like phenotype in adulthood after chronic social defeat stress. Moreover, the protein expressions of Keap1 and Nrf2 in the parietal cortex from major depressive disorder and bipolar disorder were lower than controls. These findings suggest that Keap1-Nrf2 system plays a key role in the stress resilience which is involved in the pathophysiology of mood disorders. It is, therefore, possible that dietary intake of cruciferous vegetables including glucoraphanin (or SFN) may prevent or minimize relapse from remission, induced by stress and/or inflammation in depressed patients. In the review, the author would like to discuss the role of Keap1-Nrf2 system in mood disorders.

Mechanisms of repetitive transcranial magnetic stimulation for anti-depression: Evidence from preclinical studies

“…Nuclear factor-E2-related factor 2 (Nrf2) is a transcription factor that binds to antioxidant response elements and has anti-inflammatory effects in addition to anti-oxidative stress[ 16 - 18 ]. There was significantly reduced expression of Nrf2 both in the hippocampus and prefrontal cortex (PFC) of depressive-like mice induced by chronic social defeat stress or stress susceptible rats induced by learned helplessness[ 18 , 19 ].…”

Identifying Structural Features of Sulforaphane Derivatives Based on QM Force Field for Predicting the Anti-Cancer Activity

“…(3) Using (3), the R 2 cv is obtained to be 0.554 (Table III). The cross-validated regression coefficient was found to be near to the R 2 value (0.5676) for the best correlation data set and thus this model can be accepted as statistically significant.…”

Dietary intake of glucoraphanin prevents the reduction of dopamine transporter in the mouse striatum after repeated administration of MPTP

“…Glucoraphanin (GF), which found in cruciferous vegetables, such as broccoli sprout, is a glucosinolate precursor of SFN . Previously, we reported that dietary intake of 0.1% GF food pellet could prevent the onset of psychiatric disorders such as depression and psychosis in rodents, suggesting that dietary intake of GF has prophylactic effects for development of psychiatric disorders …”

“…5,6 Accumulating evidence suggests that the transcription factor Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-Nuclear factor (erythroidderived 2)-like 2 (Nrf2) system plays a key role in inflammation which is involved in a number of neurological and psychiatric disorders. [7][8][9][10][11] Multiple lines of evidence suggest a key role of Nrf2 in the pathology of PD. [12][13][14] Jazwa et al 15 reported that sulforaphane (SFN), a potent Nrf2 activator, protects against dopaminergic neurotoxicity in mice after administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).…”

“…17 Previously, we reported that dietary intake of 0.1% GF food pellet could prevent the onset of psychiatric disorders such as depression and psychosis in rodents, [18][19][20][21] suggesting that dietary intake of GF has prophylactic effects for development of psychiatric disorders. 9 This study was undertaken to investigate whether dietary intake of 0.1% GF food pellet could prevent MPTP-induced dopaminergic neurotoxicity in the mouse striatum since MPTP-induced dopaminergic neurotoxicity is widely used as animal model of PD. 22…”