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

Nikita P Ilyin; Anton D Shevlyakov; Galina A Boyko; Anastasia M Moskalenko; Aleksey N Ikrin; David S Galstyan; Tatiana O Kolesnikova; Nataliia V Katolikova; Sergei A Chekrygin; Lee Wei Lim; LongEn Yang; Murilo S De Abreu; Konstantin B Yenkoyan; Allan V Kalueff; Konstantin A Demin

doi:10.1016/j.brainres.2024.149329

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

Brain Res. 2024 Nov 11:149329. doi: 10.1016/j.brainres.2024.149329. Online ahead of print.

Authors

Affiliations

¹ Almazov National Medical Research Centre, St. Petersburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
² Neurobiology Program, Sirius University of Science and Technology, Sochi, Russia.
³ Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
⁴ Core Facility Center "Center Bio-Bank", Saint Petersburg University, St. Petersburg, Russia.
⁵ Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China.
⁶ Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil; Western Caspian University, Baku, Azerbaijan.
⁷ Neuroscience Laboratory, Cobrain Center, Yerevan State Medical University named after Mkhitar Heratsi, 0025, Yerevan, Armenia; Biochemistry Department, Yerevan State Medical University named after Mkhitar Heratsi, 0025, Yerevan, Armenia.
⁸ Almazov National Medical Research Centre, St. Petersburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Neurobiology Program, Sirius University of Science and Technology, Sochi, Russia; Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China; Scientific Research Institute of Neurosciences and Medicine, Novosibirsk, Russia. Electronic address: [email protected].
⁹ Almazov National Medical Research Centre, St. Petersburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia. Electronic address: [email protected].

PMID: 39537125
DOI: 10.1016/j.brainres.2024.149329

Abstract

Traumatic brain injury (TBI) is a global medical concern with lasting impact on brain activity and high risks of mortality. Current treatments are inadequate for repairing damaged brain cells or correcting cognitive and behavioral disabilities in patients following TBI. 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 in a 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.

Keywords: Behavioral deficits; ISRIB; Integrated stress response; Transcriptome; Traumatic brain injury; Zebrafish.