Traumatic brain injury (TBI) carries consequences that can last a lifetime, from permanently impaired cognition and memory to increased risk of Alzheimer’s disease and other forms of dementia.
Although surgery and behavioral rehabilitation can help patients cope with ongoing symptoms, no pharmacological therapies currently exist. Researchers report that TBI causes the integrated stress response (ISR) signaling pathway to remain persistently activated in the hippocampus, a brain region implicated in memory and learning.
Furthermore, the authors demonstrate that a small molecule called ISR inhibitor (ISRIB) inhibits the core event of ISR and restores cognitive deficits in mice. Common to all eukaryotic cells, ISR acts to restore cellular homeostasis by phosphorylating eukaryotic translation initiation factor 2 (eIF2α).
Due to its small size, ISRIB readily crosses the blood–brain barrier and blunts the restoration. To determine whether sustained hippocampal eIF2α phosphorylation underpins the long-term symptoms of TBI, the authors conducted trials with two different murine models and found that ISRIB treatment is sufficient to reverse hippocampus-dependent cognitive deficits.
In addition, systemic ISRIB treatment weeks after injury enabled mice to form stable spatial memories that persisted at least 1 week after treatment stopped. Though preliminary, the findings point to a potential therapeutic path for TBI, according to the authors.
http://www.pnas.org/content/early/2017/07/05/1707661114
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