Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells

Abstract

N-acetyl serotonin (NAS) as a melatonin precursor has neuroprotective actions. Nonetheless, it is not clarified how NAS protects neuronal cells against oxidative stress. Recently, we have reported that N-palmitoyl serotonins possessed properties of antioxidants and neuroprotection. Based on those, we hypothesized that NAS, a N-acyl serotonin, may have similar actions in oxidative stress-induced neuronal cells, and examined the effects of NAS based on in vitro and in vivo tests. NAS dose-dependently inhibited oxidative stress-induced cell death in HT-22 cells. Moreover, NAS suppressed glutamate-induced apoptosis by suppressing expression of AIF, Bax, calpain, cytochrome c and cleaved caspase-3, whereas it enhanced expression of Bcl-2. Additionally, NAS improved phosphorylation of tropomyosin-related kinase receptor B (TrkB) and cAMP response element-binding protein (CREB) as well as expression of brain-derived neurotrophic factor (BDNF), whereas the inclusion of each inhibitor of JNK, p38 or Akt neutralized the neuroprotective effect of NAS, but not that of ERK. Meanwhile, NAS dose-dependently reduced the level of reactive oxygen species, and enhanced the level of glutathione in glutamate-treated HT-22 cells. Moreover, NAS significantly increased expression of heme oxygenase-1, NAD(P)H quinine oxidoreductase-1 and glutamate-cysteine ligase catalytic subunit as well as nuclear translocation of NF-E2-related factor-2. Separately, NAS at 30 mg/kg suppressed scopolamine-induced memory impairment and cell death in CA1 and CA3 regions in mice. In conclusion, NAS shows actions of antioxidant and anti-apoptosis by activating TrkB/CREB/BDNF pathway and expression of antioxidant enzymes in oxidative stress-induced neurotoxicity. Therefore, such effects of NAS may provide the information for the application of NAS against neurodegenerative diseases.

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

“…Concerning the structural importance of N ‐acyl serotonins, the neuroprotective activity of Pal‐5HT may be correlated with the length and polarity of aliphatic acyl chain. In support of this, Pal‐5HT exerted stronger neuroprotective activity than other N ‐acyl serotonins such as N ‐stearoyl serotonin and N ‐docosahexaenoyl serotonin in oxidative stress‐exposed neuronal cells, and N ‐acetyl serotonin possessed neuroprotective action in in vitro and in vivo studies . However, its effect was inferior to that of Pal‐5HT .…”

“…In support of this, Pal‐5HT exerted stronger neuroprotective activity than other N ‐acyl serotonins such as N ‐stearoyl serotonin and N ‐docosahexaenoyl serotonin in oxidative stress‐exposed neuronal cells, and N ‐acetyl serotonin possessed neuroprotective action in in vitro and in vivo studies . However, its effect was inferior to that of Pal‐5HT . Besides, lipid‐soluble molecules are known to have higher cell‐membrane permeability than polar molecules .…”

“…Recently, we reported that N ‐acetyl serotonin possessed neuroprotective activity through enhancing both the expression of antioxidant enzymes and the activation of brain‐derived neurotrophic factor (BDNF)/tropomyosin‐related kinase receptor (TrkB)/cAMP response element‐binding protein (CREB) pathway in in vitro and in vivo models of Alzheimer's disease . In this respect, we hypothesized that the neuroprotection of Pal‐5HT might be associated with the inhibition of apoptosis and the activation of BDNF/TrkB/CREB pathway.…”

BDNF as a Promising Therapeutic Agent in Parkinson’s Disease

“…By activating the IP3K/Akt kinase pathway, neurotrophins inhibit processes that elicit cell death [55][56][57]. It was found that the decrease in expression of NTs, especially BDNF observed in the aging process and in neurodegenerative diseases, may contribute to degeneration and death of neurons [58].…”

cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

“…Activated CREB promotes the expression of brain-derived neurotrophic factor (BDNF) (Yoo et al, 2017), while on the other hand, BDNF promotes the activation of CREB through tropomyosin receptor kinase (Trk) B receptors (Finkbeiner et al, 1997). Direct relationships were also found between antipsychotic drugs binding to D2R, therapeutic effect, and stimulation of CREB phosphorylation in vitro and in animal models (Konradi et al, 1993; Lee et al, 2010).…”