Neurotrauma Reports (Jul 2021)
Activation of the Protein Kinase R?Like Endoplasmic Reticulum Kinase (PERK) Pathway of the Unfolded Protein Response after Experimental Traumatic Brain Injury and Treatment with a PERK Inhibitor
Abstract
Neurodegeneration after traumatic brain injury (TBI) is increasingly recognized as a key factor contributing to poor chronic outcomes. Activation (i.e., phosphorylation) of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway has been implicated in neurodegenerative conditions with pathological similarities to TBI and may be a potential target to improve TBI outcomes. Here, we aimed to determine whether a moderate TBI would induce activation of the PERK pathway and whether treatment with the PERK inhibitor, GSK2606414, would improve TBI recovery. Male mice were administered a lateral fluid percussion injury (FPI) or sham injury and were euthanized at either 2?h, 24?h, or 1 week post-injury (n?=?5 per injury group and time point) to assess changes in the PERK pathway. In the injured cortex, there was increased phosphorylated-PERK at 2?h post-FPI and increased phosphorylation of eukaryotic translation initiation factor ? at 24?h post-FPI. We next examined the effect of acute treatment with GSK2606414 on pathological and behavioral outcomes at 4 weeks post-injury. Thus, there were a total of four groups: sham + VEH (n?=?9); sham + GSK4606414 (n?=?10); FPI + VEH (n?=?9); and FPI + GSK2606414 (n?=?9). GSK2606414 (50?mg/kg) or vehicle treatment was delivered by oral gavage beginning at 30?min post-injury, followed by two further treatments at 12-h increments. There were no significant effects of GSK2606414 on any of the outcomes assessed, which could be attributable to several reasons. For example, activation of PERK may not be a significant contributor to the neurological consequences 4 weeks post-FPI in mice. Further research is required to elucidate the role of the PERK pathway in TBI and whether interventions that target this pathway are beneficial.
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