Table 2.
The effects of Sigma1R agonists associated with antidepressant-like activity.
| Sigma1R Agonists | Effects | |
|---|---|---|
| Fluvoxamine | BDNF | Upregulation of Akt1 phosphorylation (Ser473) in vitro [177]. Increases proBDNF and mBDNF levels in the hippocampus and prefrontal cortex of rats with comorbid depression-like disorder. The effects were blocked by Sigma1R antagonist NE-100 [31]. |
| NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro [23,93,94,95]. The effect was blocked by Sigma1R antagonist NE-100 [93,94]. | |
| Calcium signaling | Causes a decrease in the immobilization time of Camk4−/− mice in the forced swim test and the tail suspension test. The effect was blocked by Sigma1R antagonist NE-100 [96]. | |
| ER stress and unfolded protein response | Increases expression of the Sigmar1 and the Atf4 genes in vitro. Inhibits apoptosis of Neuro2a cells under simulated ER stress. The effects were blocked by Sigma1R antagonist NE-100 [189]. | |
| Fluoxetine | NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro [23]. |
| Epigenetic regulation of gene expression | Normalizes the level of mir-451 in the hippocampus of rats subjected to stress at an early age (maternal separation) [190]. | |
| Escitalopram | NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro [23]. |
| Citalopram | Epigenetic regulation of gene expression | Alters the methylation of the promoter regions of TSPO and BDNF genes in vitro [191]. |
| Imipramine | BDNF | Enhances BDNF-induced glutamate release and intracellular Ca2+ increase in vitro. Stimulates of PLCγ binding to trkB and PLCγ phosphorylation in vitro. The effects were blocked by Sigma1R antagonist BD-1047 [100]. |
| NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro [95,101]. The effect was blocked by Sigma1R antagonist NE-100 [101]. | |
| DHEA | BDNF | Increases Akt1 phosphorylation (Ser473) in vitro [177]. Reduces the level of pGSK-3β (Ser9) in the hippocampal dentate gyrus of olfactory bulbectomized mice. The effect was blocked by Sigma1R antagonist NE-100 [105]. |
| NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro [103]. | |
| Glutamatergic neurotransmission | Restores the phosphorylation of GluN1 (Ser896) and GluA1 (Ser831) receptors in the hippocampal dentate gyrus and CA1 region of olfactory bulbectomized rats. The effect was blocked by Sigma1R antagonist NE-100 [104,105]. Restores levels of nNOS, NO, and p-CREB in the hippocampus of ICR mice in a model of depression induced by estrogen withdrawal (E2) under hormone-stimulated pregnancy. The effect was attenuated by Sigma1R antagonist NE-100. Experimental animals were characterized by a decrease in the BDNF protein level and phosphorylation of GluN2B (p-NR2B) in the hippocampus. The dynamics of these changes was sensitive to the effect of Sigma1R antagonist NE-100 [125]. | |
| Calcium signaling | Increases CaMKIIα phosphorylation in the hippocampus of olfactory bulbectomized mice. The effect was blocked by Sigma1R antagonist NE-100 [104,105]. | |
| Igmesine (JO-1784) |
Calcium signaling | The antidepressant-like effect of igmesine was prevented by Ca2+ channel blockers [122]. |
| Cutamesine (SA4503) |
BDNF | Increases BDNF secretion in vitro [161]. Increase in the BDNF content in the hippocampus of naïve rats [163]. |
| NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro. The effect was blocked by Sigma1R antagonist NE-100 [93]. | |
| Glutamatergic neurotransmission | Restoration of the GluN1 level in the prefrontal cortex, hippocampus, and amygdala of olfactory bulbectomized rats. The effect was blocked by Sigma1R antagonist NE-100 [110]. | |
| Calcium signaling | Causes a decrease in the immobilization time of Camk4−/− mice in the forced swim test and the tail suspension test. The effect was blocked by Sigma1R antagonist NE-100 [96]. | |
| (+)-pentazocine | NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro [95]. |
| ER stress and unfolded protein response | Causes a decrease in the expression of the genes Hspa5 (Grp78, Bip), Eif2ak3 (Perk), Atf6, Ern1 (Ire1α), and Ddit (Chop), and an increase in the Sigmar1 mRNA upon cellular stress in vitro. Blocks the stimulatory effect of the xanthine–xanthine oxidase system on the formation of the Sigma1R‒BiP complex and phosphorylation of Sigma1R [192]. | |
| Epigenetic regulation of gene expression | Decreases the level of mir-214-3p in retinal cells [193]. Mir-214-3p reduces β-catenin expression [194], while mir-214 is involved in the regulation of peroxidation processes [195,196]. | |
| (+)-SKF-10.047 | BDNF | Increases BDNF secretion in vitro. The effect was blocked by Sigma1R antagonist BD-1063 [162]. |
| PRE-084 | BDNF | Increases neurite outgrowth in vitro due to the phosphorylation of BDNF trkB receptors. The effect was blocked by Sigma1R antagonist BD-1063 [165]. Increased the level of pGSK-3β (Ser9) in the hippocampus of naïve mice [127]. |
| NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro. The effect was blocked by Sigma1R antagonist NE-100 [94]. | |
| Glutamatergic neurotransmission | Restoration of nNOS, NO, and p-CREB levels in the hippocampus of ICR mice in a model of depression induced by estrogen withdrawal (E2) under hormone-stimulated pregnancy [125]. | |
| Ketamine | NGF | Stimulates neurite outgrowth upon incubation in the presence of NGF in vitro. The effect was blocked by Sigma1R antagonist NE-100 [101]. |