Neurotranscriptomic and behavioral effects of ISRIB, and its therapeutic effects in the traumatic brain injury model in zebrafish.

Traumatic brain injury (TBI) is a global medical concern and has a lasting impact on brain activity with high risks of mortality. Current treatments are inadequate for repairing damaged brain cells or correcting cognitive and behavioral disabilities in TBI patients. Mounting evidence links TBI to the activation of the Integrated Stress Response (ISR) signaling in the brain. A novel small molecule, ISRIB, is an effective inhibitor of the ISR pathway, offering potential advantages for brain health. Here, we investigated how ISRIB affects brain transcriptome and behavior in zebrafish TBI model evoked by telencephalic brain injury. Overall, while TBI diminished memory and social behavior in zebrafish, administering ISRIB post-injury markedly reduced these behavioral deficits, and modulated brain gene expression, rescuing TBI-activated pathways related to inflammation and brain cell development. Collectively, this supports the role of brain ISR in TBI, and suggests potential utility of ISRIB for the treatment of TBI-related states.