Anti‐Apoptotic Effect of N‐Palmitoyl Serotonin on Glutamate‐Mediated Apoptosis Through Secretion of BDNF and Activation of TrkB/CREB Pathway in HT‐22 Cells

Abstract

Recently, N‐acyl serotonins have been reported to exert neuroprotective actions against oxidative stress by inducing antioxidant enzymes. However, the mechanisms for the neuroprotective action of N‐acyl serotonins are still not clarified. In this study, we focuse on the suppressive effect of N‐palmitoyl serotonin on glutamate‐induced apoptosis in HT‐22 cells, and then examine the molecular mechanism for anti‐apoptotic action of N‐palmitoyl serotonin. For this purpose, flow cytometry, immunoblotting analysis and antibody‐mediated neutralization is formed. When HT‐22 cells are preincubated with N‐palmitoyl serotonin prior to glutamate treatment, N‐palmitoyl serotonin dose‐dependently reduces apoptotic bodies, and recoveres mitochondrial potential in glutamate‐treated HT‐22 cells. Further, N‐palmitoyl serotonin concentration‐dependently increases the expression of B‐cell lymphoma 2 (Bcl‐2), an anti‐apoptotic factor, whereas it reduces the expression of Bcl‐2‐associated X protein, apoptosis‐inducing factor, Ca2+‐dependent non‐lysosomal cysteine protease, cytochrome c, and cleaves caspase‐3. Meanwhile, N‐palmitoyl serotonin enhanced phosphorylation of tropomyosin‐related kinase receptors (TrkB) and cAMP response element‐binding protein (CREB) as well as expression of brain‐derived neurotrophic factor (BDNF). Separately, the inclusion of anti‐BDNF antibody neutralizes the neuroprotective action of N‐palmitoyl serotonin against glutamate‐induced cell death. In addition, K252a, a TrkB inhibitor, also reverses neuroprotective effect of N‐palmitoyl serotonin, suggesting that the action of N‐palmitoyl serotonin may be expressed through the formation of BDNF. Based on these results, it is proposed that N‐palmitoyl serotonin promotes formation and secretion of BDNF, and then protects neuronal cells against oxidative stress‐induced apoptosis through activation of TrkB/CREB pathway.Practical Applications: The results may provide further information for the application of N‐acyl serotonins as a therapeutic or preventive agent for neurodegenerative diseases.N‐Palmitoyl 2 serotonin (Pal‐5HT) not only induces brain‐derived neurotrophic factor (BDNF) expression but also protects neuronal cells against oxidative stress.