Post‐ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia

Abstract

Ischemic stroke is one of the most important causes of death and disability worldwide. Subroutines underlying cell death after stroke are largely unknown despite their importance in the design of novel therapies for this pathology. Necroptosis, a recently described form of regulated cell death, has been related with inflammation and, in some models, with endoplasmic reticulum (ER) stress. We hypothesize that alleviation of ER stress following a salubrinal treatment will reduce the ischemic‐dependent necroptosis. To probe the hypothesis, we measured, at 48 and 72 h after transient global cerebral ischemia in rat, in cerebral cortex and cornu ammonis 1, the main hallmarks of necroptosis: mRNA levels and phosphorylation of mixed lineage kinase domain like pseudokinase as well as receptor interacting serine/threonine protein kinase 3, along the years 2017–2018. Selective neuronal loss after 7 days of the ischemic insult, and other markers related with the inflammatory response were also measured. This study shows that necroptosis in cerebral cortex can be detected after 72 h of the insult and seems to be elicited before 48 h of reperfusion. The type of necroptosis here observed seems to be tumor necrosis factor receptor 1 independent. Necroptotic response is less evident in the cornu ammonis 1 hippocampal area than in cerebral cortex. The treatment with salubrinal administered 1 and 24 h after the ischemia, decreased the necroptotic marker levels and reduced the areas of selective neuronal loss, supporting the presence of ischemic‐dependent necroptosis, and the notion that ER stress is involved in the necroptotic response. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/

Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery

“…The ratio of Sal to 4E1RCat for experimentation was based on the published literature. Specifically, Sal at 1 mg/kg has been used by multiple groups for its ability to inhibit tumor xenografts (28) and other pharmacological activities (29)(30)(31). However, 4E1RCat was not well-studied in mouse models, and hence, the dose of Sal was fixed and 4E1RCat varied to assess and maximize the combined effect.…”

Injury‐preconditioning secretome of umbilical cord mesenchymal stem cells amplified the neurogenesis and cognitive recovery after severe traumatic brain injury in rats

“…Western blotting was performed at 7 days post TBI according to an established method (Li et al 2013) (Font-Belmonte et al 2019Shinozaki et al 2019). Briefly, equal amounts of protein from rat hippocampi were separated by 12% sodium dodecyl sulfatepolyacrylamide gel (BioVision) and transferred to nitrocellulose membranes (Millipore, USA).…”

Salubrinal Protects Against Cisplatin-Induced Cochlear Hair Cell Endoplasmic Reticulum Stress by Regulating Eukaryotic Translation Initiation Factor 2α Signalling

“…Therefore, Sal can reduce ERS overexpression and block the initiation of the apoptotic program by selectively inhibiting the dephosphorylation of the PERK-eIF2α phosphate complex ( Boyce et al, 2005 ). Sal plays a cytoprotective role during ERS in various diseases ( López-Hernández et al, 2015 ; Matsuoka and Komoike, 2015 ; Font-Belmonte et al, 2019 ). Our previous studies revealed ( Zhang et al, 2015 , 2020 ) that Sal treatment improved neurological dysfunction through the inhibition of ER stress after postresuscitation brain injury.…”