Related reading:
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B
https://bohrium.dp.tech/paper/arxiv/812808606431838209
Inhibition of the Integrated Stress Response Restores Cognition After Brain Injury
A. Chou,† N. Day,‡ T. Jopson,‡ F. Cho,† C. Sidrauski,ÅòŘ
P. Walter,Ř# and S. Rosi†‡Åò*
Brain and Spinal Injury Center, University of California,
San Francisco, CA, USA
Neuroscience Graduate Program, University of California,*
San Francisco, CA, USA
Department of Physical Therapy Rehabilitation Science,
University of California, San Francisco, CA, USA
Department of Neurological Surgery, University of California,*
San Francisco, CA, USA
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA*
Howard Hughes Medical Institute, University of California,
San Francisco, CA, USA
The integrated stress response (ISR) controls mRNA translation by phosphorylation of the eukaryotic translation initiation factor eIF2.
ISRIB is a drug-like small-molecule ISR inhibitor (in-cell EC* 50 = 5 nM) that enhances memory consolidation in normal animals. Loss of cognitive functions and sustained ISR are associated with numerous neurological conditions, including traumatic brain injury (TBI). We investigated the efficacy of ISRIB on the cognitive deficits induced by TBI using two different animal models tested in two different cognitive tasks. First, focal contusion injury was induced by controlled cortical impact (CCI) in C57B6 mice. Spatial learning and memory retention were measured in the radial arm water maze starting 28 days after injury. Either ISRIB (2.5 mg/kg) or vehicle was administered intraperitoneally the day prior to and at the end of each training day for a total of three injections. In agreement with previous reports, TBI animals receiving vehicle only failed to learn the location of the escape platform. In striking contrast, ISRIB-treated TBI animals learned as well as the noninjured animals. Memory consolidation was measured 24 h and 7 days after training in the absence of any additional treatment. At both times, ISRIB-treated TBI animals remembered the location of the hidden platform indistinguishable from noninjured controls. Thus, ISRIB completely restored the ability of the injured animals to learn and remember a new task. Most importantly, this memory was fully consolidated, as it could be recalled without further treatment. Second, diffuse TBI was modeled by closed-head injury (CHI) in C57B6 mice and the delayed matching-to-place paradigm was used in a dry maze (modified Barnes maze) to assess working/ episodic-like learning and memory. Fourteen days after injury either ISRIB (2.5 mg/kg) or vehicle was administered intraperitoneally prior to and then again at the end of each training day for a total of four injections. As for the CCI experiments, ISRIB-treated animals performed indistinguishable from uninjured controls, indicating that ISRIB treatment completely reversed the deficits induced by CHI. We conclude that in these models targeting the ISR at time points late after injury can completely reverse chronic loss of cognitive functions induced by head trauma.*
