ArticleACS chemical biology2021
Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2.
Article in ACS chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 37 citations in OpenAlex.
- Mapping the secondary response to traumatic brain injury using spatial transcriptomics shows acute 4-aminopyridine treatment mitigates axonal and molecular pathology.Acta neuropathologica communications · 2026Article
- Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm.Cell death & disease · 2025Review
- AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss.Glia · 2025Article
- Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.Cell reports. Medicine · 2025Article
- Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation.Israel journal of chemistry · 2024Article
- Metabolically activated proteostasis regulators that protect against erastin-induced ferroptosis.RSC chemical biology · 2024Article
- A Novel Analog of the Natural Product Fraxinellone Protects against Endogenous and Exogenous Neurotoxicants.ACS chemical neuroscience · 2024Article
- Mapping stress-responsive signaling pathways induced by mitochondrial proteostasis perturbations.Molecular biology of the cell · 2024Article
- Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.bioRxiv : the preprint server for biology · 2024Article
- Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.Cell chemical biology · 2023Article
- Protocadherin 20 maintains intestinal barrier function to protect against Crohn's disease by targeting ATF6.Genome biology · 2023Article
- Optimization of 3-aminotetrahydrothiophene 1,1-dioxides with improved potency and efficacy as non-electrophilic antioxidant response element (ARE) activators.Bioorganic & medicinal chemistry letters · 2023Article
- Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells.bioRxiv : the preprint server for biology · 2023Article
- mTOR/α-ketoglutarate signaling: impact on brain cell homeostasis under ischemic conditions.Frontiers in cellular neuroscience · 2023Review
- Ameliorative Effects of Peptide Phe-Leu-Ala-Pro on Acute Liver and Kidney Injury Caused by CClACS omega · 2022Article
- Protein quality control ofFrontiers in cellular neuroscience · 2022Review
- AA147 ameliorates post-cardiac arrest cerebral ischemia/reperfusion injury through the co-regulation of the ATF6 and Nrf2 signaling pathways.Frontiers in pharmacology · 2022Article
- Preventive Effect of Collagen Peptides fromOxidative medicine and cellular longevity · 2022Article
- Role of Nrf2 in Parkinson's Disease: Toward New Perspectives.Frontiers in pharmacology · 2022Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The extracellular accumulation of glutamate is a pathologic hallmark of numerous neurodegenerative diseases including ischemic stroke and Alzheimer's disease. At high extracellular concentrations, glutamate causes neuronal damage by promoting oxidative stress, which can lead to cellular death. This has led to significant interest in developing pharmacologic approaches to mitigate the oxidative toxicity caused by high levels of glutamate. Here, we show that the small molecule proteostasis regulator AA147 protects against glutamate-induced cell death in a neuronal-derived cell culture model. While originally developed as an activator of the activating transcription factor 6 (ATF6) arm of the unfolded protein response, this AA147-dependent protection against glutamate toxicity is primarily mediated through activation of the NRF2-regulated oxidative stress response. We demonstrate that AA147 activates NRF2 selectively in neuronal-derived cells through a mechanism involving metabolic activation to a reactive electrophile and covalent modification of KEAP1─a mechanism analogous to that involved in the AA147-dependent activation of ATF6. These results define the potential for AA147 to protect against glutamate-induced oxidative toxicity and highlight the potential for metabolically activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 stress-responsive signaling pathways to mitigate oxidative damage associated with diverse neurologic diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.