Rg1 in combination with mannitol protects neurons against glutamate-induced ER stress via the PERK-eIF2 α-ATF4 signaling pathway.

Ginseng and ginsenosides are known for their remarkable effects on the central nervous system. However, pharmacokinetic studies have suggested that the Ginsenoside Rg1 (Rg1) cannot be efficiently transported through the blood-brain barrier. To investigate the effects of Rg1 in combination with mannitol protects neurons against glutamate-induced ER stress via the PERK-eIF2 -ATF4 signaling pathway. Rg1, along with the BBB permeabilizer mannitol, exhibited a potent neuroprotective effect by significantly reducing the neurological scores and infarct volume in rats exposed to middle cerebral artery occlusion. We evaluated the effect of Rg1 on neuroprotection after MCAO, and also explored its potential mechanism of action. Our results show that Rg1 reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons. This neuroprotection may be dependent, at least in part, on the preservation of the endoplasmic reticulum and mitochondrial function. Ischemia-induced brain injury is largely caused by the excessive release of glutamate, which results in excitotoxicity and cell death. Neurons were pretreated with Rg1 before inducing endoplasmic reticulum stress with glutamate. A reduction in the expression of Bax and a concomitant increase in Bcl2 expression prevented the induction of apoptosis. Furthermore, Rg1 downregulated the expression of endoplasmic reticulum stress genes. Our results indicate that Rg1 modulation of stress-responsive genes helps prevent glutamate-induced endoplasmic reticulum stress in neurons through the PERK-eIF2-α-ATF4 signaling pathway.

Gu Y ，Ren K ，Wang L ，Jiang C ，Yao Q ... -  《-》

Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress.

Lin YW ，Chen TY ，Hung CY ，Tai SH ，Huang SY ，Chang CC ，Hung HY ，Lee EJ ... -  《-》

Wogonin protects rat dorsal root ganglion neurons against tunicamycin-induced ER stress through the PERK-eIF2α-ATF4 signaling pathway.

Chen F ，Wu R ，Zhu Z ，Yin W ，Xiong M ，Sun J ，Ni M ，Cai G ，Zhang X ... -  《-》

Alpha-lipoic acid protects against cadmium-induced neuronal injury by inhibiting the endoplasmic reticulum stress eIF2α-ATF4 pathway in rat cortical neurons in vitro and in vivo.

The heavy metal cadmium (Cd) is well known to be neurotoxic. Studies have shown that apoptosis plays an essential role in Cd-induced brain injury; however, the mechanisms underlying this injury accompanied by apoptosis have yet to be elucidated. The endoplasmic reticulum (ER) stress plays a key part in the regulation of apoptosis. ER stress is defined as accumulation of unfolded or misfolded proteins in the ER. Here, we demonstrated the role of ER stress on Cd-evoked apoptosis in neuronal cells, as well as the neuroprotective effects of the antioxidant alpha-lipoic acid (α-LA) on Cd-induced ER stress and neuronal injury. In vitro, we observed that Cd activated ER associated proteins via the eIF2α-ATF4 pathway in primary rat cerebral cortical neurons. Furthermore, the ER-stress inhibitor salubrinal blocked the dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and significantly reduced the induction of ER stress marker CHOP, the increase of the B-cell lymphoma-2 associate X protein (Bax)/B-cell lymphoma-2 (Bcl-2) ratio, and apoptosis induced by Cd. In addition, Z-ATAD-FMK (a caspase-12 inhibitor) counteracted the Cd-induced activation of caspase-12 and -3, and apoptosis. These in vitro results collectively suggested that ER stress was required for Cd-induced neuronal apoptosis. Importantly, α-LA inhibited the activation of the ER stress eIF2α-ATF4 pathway, the increase of the Bax/Bcl-2 ratio, the activation of caspase-12 and -3, and the apoptosis induced by Cd. In vivo, we also found that the administration of α-LA alleviated Cd-induced neuronal injury, inhibited the activation of the ER stress eIF2α-ATF4 pathway, restored the Bax/Bcl-2 ratio, and prevented the activation of caspase-12 and -3. Taken together, our results demonstrated that Cd triggered protein changes in the ER accompanied by apoptosis via the eIF2α-ATF4 signaling pathway in the neuronal cells of rats, both in vitro and in vivo. Furthermore, we demonstrated for the first time that α-LA protected neurons from Cd-induced injury partly by inhibiting ER stress in rat cerebral cortical neurons.

Yuan Y ，Yang J ，Chen J ，Zhao S ，Wang T ，Zou H ，Wang Y ，Gu J ，Liu X ，Bian J ，Liu Z ... -  《-》

The Role of the GRP78/PERK/ATF4 Pathway in the Ability of Gua Lou Gui Zhi Decoction to Attenuate Apoptosis by Inhibiting Endoplasmic Reticulum Stress after Ischemia-Reperfusion Injury.

Endoplasmic reticulum stress (ERS) is a key part of the apoptotic cascade that is initiated after cerebral ischemia-reperfusion injury and is very important for research on poststroke rehabilitation. In addition, the unfolded protein response (UPR) plays an important role in ERS because it activates downstream apoptotic signal transduction and induces apoptosis through the glucose-regulated protein 78 (GRP78)/protein kinase R (PKR)-like ER kinase (PERK)/activating transcription factor 4 (ATF4) pathway. The Gua Lou Gui Zhi Decoction (GLGZD) ameliorated neuronal apoptosis of ischemia-reperfusion injury caused by middle cerebral artery occlusion (MCAO) had been proved in our previous study. The present study aims to underly the regulatory ability of GLGZD in ERS-induced apoptosis mediated by the GRP78/PERK/ATF4 pathway. GLGZD was analyzed by HPLC. The effects of GLGZD were obversed on MCAO-induced ischemic rats. The cerebral infarct volume was detected by 2,3,5-Triphenyl-2H-Tetrazolium Chloride (TTC) Staining. Terminal Deoxynucleotidyl Transferase-Mediated dUTP-Biotin Nick End Labeling (TUNEL) were used to detect apoptosis. Transmission Electron Microscopy (TEM), Ca2+ levels and reactive oxygen species (ROS) detection were used to determine the function of endoplasmic reticulum. The GRP78/PERK/ATF4 signaling pathway was assessed by western blotting and immunohistochemistry. Our results showed that GLGZD exerted its effects on ischemia-reperfusion injury by significantly promoting the restoration of the quantity and morphology of the rough ER and reducing the neuronal apoptosis rate in the ischemic cortex. Moreover, both of the intracellular ROS and Ca2+ levels in ischemic cortical cells were found significantly reduced by GLGZD. The GLGZD-treated group showed increased levels of phosphorylation in both of PERK and eukaryotic translation initiation factor 2α (eIF2α), activation of cysteinyl aspartate-specific proteinase-3 (Caspase-3), upregulation of the total protein levels of sarcoplasmic/endoplasmic Ca2+ ATPase 2α (SERCA 2α) and B-cell leukemia/lymphoma gene 2 (Bcl-2). These findings suggest that GLGZD reduces oxidative stress-induced injury and promotes a dynamic calcium balance, thereby inhibiting ERS and exerting an antiapoptotic effect on neuronal ischemic injury, which are closely related to the activation of GRP78/PERK/ATF4 signaling pathway.

Chen Y ，Chen Z ，Cheng W ，Cao Y ，Xu W ，Lai W ，Zhang Y ，Huang M ，Nan L ... -  《-》