Endoplasmic Reticulum Stress Causing Apoptosis in a Mouse Model of an Ischemic Spinal Cord Injury

Abstract

A spinal cord injury (SCI) is the devastating trauma associated with functional deterioration due to apoptosis. Most laboratory SCI models are generated by a direct impact on an animal’s spinal cord; however, our model does not involve the direct impact on the spinal cord. Instead, we use a clamp compression to create an ischemia in the descending aortas of mice. Following the success of inducing an ischemic SCI (ISCI), we hypothesized that this model may show apoptosis via an endoplasmic reticulum (ER) stress pathway. This apoptosis by the ER stress pathway is enhanced by the inducible nitric oxide synthase (iNOS). The ER is used for the protein folding in the cell. When the protein folding capacity is overloaded, the condition is termed the ER stress and is characterized by the accumulation of misfolded proteins inside the ER lumen. The unfolded protein response (UPR) signaling pathways that deal with the ER stress response then become activated. This UPR activates the three signal pathways that are regulated by the inositol-requiring enzyme 1α (IRE1α), the activating transcription factor 6 (ATF6), and the protein kinase RNA-like ER kinase (PERK). IRE1α and PERK are associated with the expression of the apoptotic proteins. Apoptosis caused by an ISCI is assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) test. An ISCI also reduces synaptophysin and the neuronal nuclear protein (NeuN) in the spinal cord. In conclusion, an ISCI increases the ER stress proteins, resulting in apoptosis in neuronal cells in the spinal cord.

Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism

“…GSH, an essential intracellular thiol tripeptide present in mammalian tissues, serves as a critical nucleophilic scavenger and enzyme-catalyzed antioxidant, particularly in response to electrophilic/oxidative tissue damage ( Soni et al, 2023 ). Its deficiency has been implicated in various diseases, including cancer, neurodegenerative diseases, cystic fibrosis, viral infections including HIV-1, respiratory distress syndrome, and aging diseases ( Ruffmann and Wendel, 1991 ).…”

“…Consistently, we found that GSH administration reduced the abnormal elevation of NO induced by AHE modeling in the cortex. Furthermore, ER stress can induce apoptosis or inflammation through one or more of the three pathways, mainly including PERK-ATF4, IRE1-XBP1s or ATF6 ( Soni et al, 2023 ). Given the association between iNOS and ER stress-induced apoptosis, we measured ER stress-related genes (ATF4, IRE1α, and ATF6) to further verify the crucial role of iNOS in AHE.…”

“…More treatment options and preventive nursing interventions are needed to decrease the incidence of HE and reduce its socio-economic impact on families and pressure on medical resources. Glutathione (GSH), an endogenous hydrophilic antioxidant, has demonstrated efficacy in shielding from various reactive oxygen species and nitrogen species ( Soni et al, 2023 ). Disruptions in GSH homeostasis have been proven to be closely related to the pathogenesis of various diseases, including obesity, diabetes, ischemic stroke, and other neurodegenerative diseases ( Johnson et al, 2012 ; Nikolaos et al, 2018 ).…”