Trans-ISRIB 25mg – 60 capsules (presale)

Trans-ISRIB 25 mg — 60 oral research capsules (presale). Trans-ISRIB is one of the most pharmacologically remarkable small molecules to emerge from academic neuroscience in the past two decades — and arguably the single most striking cognitive rescue agent ever characterized. Discovered in the laboratory of Peter Walter at UC San Francisco, ISRIB (Integrated Stress Response InhiBitor) reverses the integrated stress response (ISR) — a near-universal cellular signaling pathway that, when chronically activated, suppresses translation of proteins required for memory consolidation. In landmark rodent studies, single-dose oral trans-ISRIB has produced complete reversal of cognitive deficits caused by traumatic brain injury, Alzheimer’s-like pathology, Down syndrome models, aging and pre-existing memory impairment — restoring performance to that of young, healthy controls within hours.

Research Overview

The integrated stress response (ISR) is an ancient, evolutionarily conserved cellular signaling pathway in which four distinct kinases (PERK, GCN2, HRI, PKR) — each responsive to a different cellular stressor (ER stress, amino-acid depletion, heme deficiency, viral infection) — converge to phosphorylate the alpha subunit of eIF2 (eIF2α), suppressing global protein translation [1]. This shutdown is adaptive in the short term but profoundly maladaptive when chronic — and chronic ISR activation has now been documented in normal aging, traumatic brain injury, Alzheimer’s disease, ALS, prion disease, Down syndrome, vanishing white matter disease and even cognitive decline associated with COVID-19 “brain fog” [1,2]. Trans-ISRIB, discovered in the Walter laboratory at UCSF, is a small-molecule allosteric activator of the eIF2 guanine-nucleotide-exchange factor eIF2B that selectively reverses ISR-mediated translation suppression while leaving the four upstream kinase signals intact [1]. In the published in-vivo work — Sidrauski et al., eLife 2013; Chou et al., PNAS 2017; Krukowski et al., eLife 2020 — single oral doses of trans-ISRIB have produced complete reversal of cognitive deficits in TBI, aging, Down-syndrome and Alzheimer’s-pathology mouse models, with effects persisting for days after a single administration [2,3]. The compound is the founding member of an entirely new pharmacological category and has emerged as one of the most important neuropharmacological research tools of the past decade.

Primary Research Areas

• Integrated Stress Response (ISR) pharmacology — the founding small-molecule eIF2B activator and the principal chemical probe for studying ISR pharmacology — an entirely new therapeutic category [1,2].
• Traumatic brain injury and cognitive rescue — single-dose oral trans-ISRIB reverses TBI-induced memory deficits weeks after the inciting injury in rodent models [3].
• Aging and age-related cognitive decline — complete restoration of young-adult-level memory performance in aged mice with single administration [3].
• Alzheimer’s disease and Down syndrome models — investigated for cognitive-deficit rescue in genetically modified rodent models of both conditions [2].
• Vanishing white matter disease and prion disease — the principal clinical-translational target indications, with active drug-development programs derived from trans-ISRIB scaffold [1,2].

References

1. Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife. 2013;2:e00498.
2. Chou A, Krukowski K, Jopson T, et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc Natl Acad Sci USA. 2017;114(31):E6420–E6426.
3. Krukowski K, Nolan A, Frias ES, et al. Small molecule cognitive enhancer reverses age-related memory decline in mice. eLife. 2020;9:e62048.