Inhibition of Glycogen Synthase Kinase 3β as a Treatment for the Prevention of Cognitive Deficits after a Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) has many long-term consequences, including impairment in memory and changes in mood. Glycogen synthase kinase 3b (GSK-3b) in its phosphorylated form (p-GSK-3b) is considered to be a major contributor to memory problems that occur post-TBI. We have developed an antisense that targets the GSK-3b (G AO) gene. Using a model of closed-head concussive TBI, we subjected mice to TBI and injected G AO or a random antisense (R AO) 15 min post-injury. One week post-injury, mice were tested in object recognition with 24 h delay. At 4 weeks post-injury, mice were tested with a T-maze foot shock avoidance memory test and a second object recognition test with 24 h delay using different objects. Mice that received G AO show improved memory in both object recognition and T-maze compared with R AO-treated mice that were subjected to TBI. Next, we verified that G AO blocked the surge in phosphorylated GSK-3b post-TBI. Mice were subjected to TBI and injected with antisense 15 min post-TBI with G AO or R AO. Mice were euthanized at 4 and 72 h post-TBI. Analysis of p-ser9GSK-3b, p-tyr216GSK-3b, and phospho-tau (p-tau) 404 showed that mice that received a TBI+ R AO had significantly higher p-ser9GSK-3b, p-tyr216GSK-3b, and p-tau 404 levels than the mice that received TBI+ G AO and the Sham+ R AO mice. The current finding suggests that inhibiting GSK-3b increase after TBI with an antisense directed at GSK-3b prevents learning and memory impairments.

Enhanced Akt/GSK‐3β/CREB signaling mediates the anti‐inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice

“…VuPAM treatment also increased the expression of pCREB and anti‐inflammatory YM1 in GFP+ microglia in the injured cortex. Notably, other pre‐clinical TBI studies have implicated the activation of Akt/GSK‐3β (Farr, Niehoff, Kumar, Roby, & Morley, 2019; Jiang et al, 2017; Wang, Shi, & Jiang, 2015) and CREB (Alexaki et al, 2018) signal transduction pathways in the suppression of pro‐inflammatory and neurotoxic neuroinflammation, as well as for promotion of anti‐inflammatory and neuroprotective responses following moderate‐severe TBI.…”

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“…It suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. Consistently, those primary kinases have also involved in the pathogenesis of TBI [10][11][12], although there are differences in the pathogenesis of TBI and AD.…”

The Nanotheranostic Researcher’s Guide for Use of Animal Models of Traumatic Brain Injury

“…T and Y mazes are similar, based on the same principle of spatial learning and memory. Both mazes function as a two-pronged maze using either positive stimuli (e.g., food, novel objects) [ 85 – 87 ] or negative stimuli (e.g., light, electrical shock and sound, a blocked arm) [ 88 , 89 ] to promote memorization of the different arms. After training, the stimuli are removed, and animals are tested again to measure memory.…”