ISRIB

ISRIB is an inhibitor of the protein kinase R-like endoplasmic reticulum kinase (PERK) signaling pathway. ISRIB effectively reverses the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α), with an IC₅₀ value of 5nM^[1]. ISRIB is an inhibitor of the integrated stress response (ISR), which restores protein synthesis suppressed under stress conditions by modulating eIF2α activity, thus exerting neuroprotective effects and improving cognitive function^{[2, 3]}.

In vitro, treatment of U2OS cells with ISRIB (200nM) specifically blocked the formation of stress granules (SGs) induced by eIF2α phosphorylation^[4]. Pretreatment of the myeloid leukemia cell line K562 with ISRIB (0-1000nM) for 2h significantly reduced the mRNA levels of ISR markers (CHOP and GADD34)^[5].

In vivo, ISRIB (2.5mg/kg) administered intraperitoneally to a mouse model of traumatic brain injury (TBI) significantly improved spatial learning and memory performance in the Morris water maze test^[6]. ISRIB (0.25mg/kg) administered intraperitoneally to prion-infected mice reduced the levels of transcription factor ATF4 in the brain and partially restored protein synthesis rates, preventing hippocampal neuronal loss and reducing typical prion-related spongiform encephalopathy^[7].

References:
[1] Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory[J]. elife, 2013, 2: e00498.
[2] Ilyin N P, Nikitin V S, Kalueff A V. The Role of the Integrated Stress Response (ISR) in Neuropsychiatric Disorders[J]. Journal of Evolutionary Biochemistry and Physiology, 2024, 60(6): 2215-2240.
[3] Costa-Mattioli M, Walter P. The integrated stress response: From mechanism to disease[J]. Science, 2020, 368(6489): eaat5314.
[4] Sidrauski C, McGeachy A M, Ingolia N T, et al. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly[J]. elife, 2015, 4: e05033.
[5] Dudka W, Hoser G, Mondal S S, et al. Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells[J]. BMC cancer, 2022, 22(1): 1254.
[6] Chou A, Krukowski K, Jopson T, et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury[J]. Proceedings of the National Academy of Sciences, 2017, 114(31): E6420-E6426.
[7] Halliday M, Radford H, Sekine Y, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity[J]. Cell death & disease, 2015, 6(3): e1672-e1672.