Melatonin Modulates Neuronal Cell Death Induced by Endoplasmic Reticulum Stress under Insulin Resistance Condition

Abstract

Insulin resistance (IR) is an important stress factor in the central nervous system, thereby aggravating neuropathogenesis and triggering cognitive decline. Melatonin, which is an antioxidant phytochemical and synthesized by the pineal gland, has multiple functions in cellular responses such as apoptosis and survival against stress. This study investigated whether melatonin modulates the signaling of neuronal cell death induced by endoplasmic reticulum (ER) stress under IR condition using SH-SY5Y neuroblastoma cells. Apoptosis cell death signaling markers (cleaved Poly [ADP-ribose] polymerase 1 (PARP), p53, and Bax) and ER stress markers (phosphorylated eIF2α (p-eIF2α), ATF4, CHOP, p-IRE1, and spliced XBP1 (sXBP1)) were measured using reverse transcription-PCR, quantitative PCR, and western blottings. Immunofluorescence staining was also performed for p-ASK1 and p-IRE1. The mRNA or protein expressions of cell death signaling markers and ER stress markers were increased under IR condition, but significantly attenuated by melatonin treatment. Insulin-induced activation of ASK1 (p-ASK1) was also dose dependently attenuated by melatonin treatment. The regulatory effect of melatonin on neuronal cells under IR condition was associated with ASK1 signaling. In conclusion, the result suggested that melatonin may alleviate ER stress under IR condition, thereby regulating neuronal cell death signaling.

Melatonin protects mouse testes from palmitic acid‐induced lipotoxicity by attenuating oxidative stress and DNA damage in a SIRT1‐dependent manner

“…4 In particular, oxidative stress is a major cause of male infertility because testicular tissue has a very high rate of cell division and mitochondrial oxygen consumption as well as higher levels of fatty acids compared to other tissues. 35 Melatonin is a well-known powerful antioxidant and is an endogenous hormone involved in multiple cellular processes such as metastasis, 36 proliferation, 37 and apoptosis. 38 However, it is still unclear whether melatonin attenuates PAinduced damage in testicular cells.…”

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

“…It has been documented that melatonin modulates the signalling of neuronal cell death [47] and bladder cancer cells induced by ERS [48]. Melatonin significantly reverses tunicamycin-induced ERS in human hepatocellular carcinoma cells and improves cytotoxic responses to doxorubicin by increasing the expression of CHOP [49].…”

Melatonin attenuates detrimental effects of diabetes on the niche of mouse spermatogonial stem cells by maintaining Leydig cells

“…Melatonin, is an indole synthesized and secreted by the pineal gland; its concentrations in the blood vary daily and seasonally in mammals 20 , 21 . Melatonin prevents various ERS-related diseases and restores the cells damage caused by ERS 22 , 23 . Melatonin also plays a significant role in the regulation of self-renewal and differentiation of various stem cells, including mesenchymal stem cells 24 and spermatogenic cells 25 .…”