Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage

Abstract

Neuronal apoptosis is an important factor accounting for the poor outcomes of intracerebral hemorrhage (ICH). This study first showed that inhibition of activating transcription factor 6 (ATF6) could alleviate secondary brain injury through anti-apoptosis after ICH in rats. Melatonin, ATF6 and CCAAT/enhancer-binding protein homologous protein (CHOP) siRNAs were applied in this study. Brain edema, neurological functions, blood-brain barrier (BBB) integrity were evaluated at 24 h after ICH. Western blot analysis was used to evaluate the protein level of target proteins (ATF6, CHOP, Bip, Bcl-2, Bax, and cleaved caspase-3). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA level of ATF6, CHOP and cleaved caspase-3. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 immunofluorescence staining were applied to evaluate the neuronal cell death. The results suggested that the levels of ATF6 and its downstream protein, CHOP, were upregulated and reached the peak at 24 h after ICH. ATF6 was highly expressed in neurons. The administration of melatonin significantly decreased the mRNA and protein levels of ATF6, and its downstream targets, CHOP and cleaved caspase-3, but increased the Bcl-2/Bax ratio, which ameliorated the neurological functions. The CHOP siRNA significantly reversed the pro-apoptotic effect induced by the increased ATF6 level after ICH. Melatonin could protect against neuronal apoptosis via suppression of ATF6/CHOP arm of ER-stress-response pathway.

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

“…The study confirms that DDT exerted a neuroprotective effect when it is pretreated in the neuronal cells and the pretreated cells showed less ER stress, Ca 2+ overload and mitochondrial apoptosis. In addition to the role of PERK and ATF6 involvement in ICH as stated in the aforementioned two studies, this study clarified the role of the inhibition of evolutionarily conserved ER stress sensor, IRE1, and its neuroprotective effect in rats and the neuronal cell model of ICH [122]. One other study explained the role of ATF6 in ICH.…”

Psoralen inhibits malignant proliferation and induces apoptosis through triggering endoplasmic reticulum stress in human SMMC7721 hepatoma cells

“…ATF6 is a type II transmembrane protein of the endoplasmic reticulum, which is separated from GRP78 and can be activated by S1P and S2P cleavage during ER-stress. Activated ATF6 promotes transcription and expression of CHOP in the nucleus, thereby inhibiting Bcl-2 and causing apoptosis [48]. This results suggested that psoralen-induced endoplasmic reticulum stress mainly activates the IRE1 pathway and the ATF6 pathway.…”

The role of melatonin in targeting cell signaling pathways in neurodegeneration

“…Autophagy can be modulated by ER stressors that can either promote cell survival or induce cell death, suggesting the interplay between autophagy and apoptosis‐related proteins. The capability of melatonin to regulate the autophagic, mitophagic, and apoptotic processes via suppression of the ATF6/CHOP pathway affirms that this indoleamine can essentially control the crosstalk between the main ER stress‐associated mechanisms . Moreover, a recent study demonstrated that melatonin provides protection against ER stress/autophagy‐induced apoptotic cell death observed in ischemic diseases by enhancing cellular prion protein (PrP C ) expression and preserving SIRT1 expression thereby counteracting both ER and oxidative stress .…”