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Inhibition of GSK-3β as a Treatment for the Prevention of Cognitive Deficits After a Traumatic Brain Injury

Inhibition of GSK-3β as a Treatment for the Prevention of Cognitive Deficits After a Traumatic Brain Injury

Journal of Neurotrauma 2019

Traumatic brain injury (TBI) has many long-term consequences including impairment in memory and changes in mood. GSK-3β in its phosphorylated form (p-GSK-3β) is considered to be a major contributor to memory problems that occur with TBI. We have developed an antisense which targets the GSK-3β (GAO) gene. Using a model of closed head concussive TBI, we subjected mice to TBI and injected GAO or a random antisense (RAO) 15 minutes post-injury. One week post-injury mice were tested in object recognition with 24 hour delay. At 4 weeks post injury mice were tested in T-maze foot shock avoidance memory test and a second object recognition test with 24 hour delay using different objects. Mice which received GAO show improved memory in both object recognition and T-maze compared to RAO treated mice that were subjected to TBI. Next, we verified that GAO blocked the surge in phosphorylated GSK-3β post-TBI. Mice were subjected to TBI and injected with antisense 15 minutes post-TBI with GAO or RAO. Mice were sacrificed at 4 and 72 hours post-TBI. Analysis of p-ser9GSK-3β, p-tyr216GSK-3β and p-Tau404 showed that mice which received a TBI+RAO had significantly higher p-ser9GSK-3β, p-tyr216GSK-3β and p-Tau404 levels than the mice which received TBI+GAO and the Sham+RAO mice. The current finding suggests that inhibiting GSK-3β increase after TBI with an antisense directed at GSK-3β prevents the learning and memory impairments.

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Accession: 066446475

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PMID: 30704365

DOI: 10.1089/neu.2018.5999

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