Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 cells via a mechanism involving the sigma-1 receptor

Chaperone Sigma1R and Antidepressant Effect

“…SSRIs are considered to act as Sigma1R agonists [89,90]. Nevertheless, studies in Sigmar1 knockout (Sigmar1 −/− ) mice indicate the possibility of SSRIs to act as inverse agonists or antagonists of Sigma1R [91,92], which is consistent with the results of in vitro studies (Table 1) [23,93,94]. enhances the expression of subunits (GluN2A, GluN2B) and the traffic of NMDA receptors to the plasma membrane of neurons [84] and regulates the activity of various types of Ca 2+ channels [85,86].…”

“…SSRIs are considered to act as Sigma1R agonists [89,90]. Nevertheless, studies in Sigmar1 knockout (Sigmar1 −/− ) mice indicate the possibility of SSRIs to act as inverse agonists or antagonists of Sigma1R [91,92], which is consistent with the results of in vitro studies (Table 1) [23,93,94].…”

“…Under the same conditions, Sigma1R agonists 4-PPBP (0.1-10 µM), SA4503 (0.1-10 µM), and antidepressants fluvoxamine (1.0 and 10 µM), fluoxetine (1.0 and 10 µM), and escitalopram (1.0 µM) also increased the length of neurites [23,93]. The selective agonist PRE-084 (1.0 µM) increased the length of neurites upon co-incubation of PC12 cells with NGF (50 ng/mL) for 24 h [94]. However, paroxetine and sertraline had no stimulatory effect, and at a concentration of 10 µM, they showed cytotoxicity, which was more pronounced for sertraline [23,93,94].…”

“…However, paroxetine and sertraline had no stimulatory effect, and at a concentration of 10 µM, they showed cytotoxicity, which was more pronounced for sertraline [23,93,94]. The stimulating effect of Sigma1R ligands on neurite outgrowth at the most effective concentrations was eliminated or mitigated significantly by the Sigma1R antagonist NE-100 (1.0 µM) [23,[93][94][95]103]. It is interesting that the addition of selective Sigma1R agonist PRE-084 (0.3 µM) or antagonist NE-100 (1.0 µM) to the incubation medium mitigated the cytotoxic effect of sertraline (1.0 µM).…”

“…The selective agonist PRE-084 (1.0 µM) increased the length of neurites upon co-incubation of PC12 cells with NGF (50 ng/mL) for 24 h [94]. However, paroxetine and sertraline had no stimulatory effect, and at a concentration of 10 µM, they showed cytotoxicity, which was more pronounced for sertraline [23,93,94]. The stimulating effect of Sigma1R ligands on neurite outgrowth at the most effective concentrations was eliminated or mitigated significantly by the Sigma1R antagonist NE-100 (1.0 µM) [23,[93][94][95]103].…”