Cell lines

PC12 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0.5-100 μM for 36 hours

Applications

Salubrinal inhibited eIF2a dephosphorylation mediated by a herpes simplex virus protein and blocked viral replication. Salubrinal dose-dependently protected PC12 cells against endoplasmic reticulum (ER) stress-induced apoptosis. Moreover, Salubrinal induced eIF2α phosphorylation and selectively inhibited eIF2α dephosphorylation.

Animal models

Rat model;

Dosage form

100 μM for 1-12 hours; i.c.v. administration

Applications

Salubrinal increased deep slow wave sleep and reduced active waking compared with the vehicle. Salubrinal increased expression of p-eIF2α in the basal forebrain (BF) area, a sleep-wake regulatory brain region [2]. Moreover, Salubrinal induced sleep by activating sleep-promoting neurons and inhibiting wake-promoting neurons in the basal forebrain (BF) and hypothalamus [3].

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

IC50: A cell-permeable and selective inhibitor of eIF2α dephosphorylation with an IC50 of 15 M.

The eukaryotic translation initiation factor 2 subunit α (eIF2α) is crucial in protein synthesis. eIF2α phosphorylation played an important role in protecting cells from apoptosis. Salubrinal selectively suppresses the phosphatase complexes that dephosphorylate eIF-2α. [1]

In vitro: This agent is reported to protect cells from endoplasmic reticulum (ER) stress-induced apoptosis (EC50 ~15 M) in PC12 cell lines induced with the protein glycosylation inhibitor tunicamycin and brefeldin A, which causes ER stress by blocking ER-to-Golgi vesicle transport. Salubrinal is a potentially useful agent to study mechanisms of ER stress-induced apoptosis. In addition, it was reported that salubrinal at 50 μM prevented cells from the autophagic and apoptotic progresses induced by loss of Bcl-2 function in murine leukemia L1210 cells. [1]

In vivo: Study from male ICR mice showed that salubrinal significantly aggravated the cisplatin-induced nephrotoxicity. In the kidneys of cisplatin-treated mice, the phosphorylation of eIF2α was significantly increased by salubrinal. In addition, the expression of CCAAT/enhancer binding protein, activating transcription factor 4 as well as the cleavage of caspases 3, 9 and 12 were also up-regulated. Moreover, salubrinal also increased the cisplatin-induced oxidative stress. These findings indicated that salubrinal aggravated cisplatin-induced nephrotoxicity via the up-regulation of ER stress-related cell apoptosis and oxidative stress. [2]

Clinical trial: So far, no clinical trial has been conducted.

References:
[1] Kessel D.  Protection of Bcl-2 by salubrinal. Biochem Bioph Res Co. 2006; 346: 1320-3.
[2] Wu CT, Sheu ML, Tsai KS, Chiang CK and Liu SH.  Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a mouse model. Free Radic Biol Med, 2011; 51(3): 671-680.