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Cited by 156Neuroscience and Neuropharmacology ResearchAmino Acid Enzymes and MetabolismAmyotrophic Lateral Sclerosis Research

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

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Kong, Qiongman, Chang, Ling-Chu, Takahashi, Kou, Liu, Qibing, Schulte, Delanie A., Lai, Liching, Ibabao, Brian, Lin, Yuchen +7 more·2014·Journal of Clinical Investigation
DOI 10.1172/jci66163PMC PMC3938250
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Abstract

Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.

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Authors
Kong, Q., Chang, L.-C., Takahashi, K., Liu, Q., Schulte, D. A., Lai, L., Ibabao, B., Lin, Y., Stouffer, N., Mukhopadhyay, C. D., Xing, X., Seyb, K. I., Cuny, G. D., Glicksman, M. A., & Lin, C.-L. G.
Affiliations
  • The Ohio State University (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Lin, Chien-Liang Glenn
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2014-02-24
Volume
124
Issue
3
Pages
1255-1267
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci66163
PMC
PMC3938250
OpenAlex
W2037230855
Cited by
156
References
3
Citations by year
2026: 9 · 2025: 11 · 2024: 17 · 2023: 14 · 2022: 12 · 2021: 10 · 2020: 16 · 2019: 11 · 2018: 14 · 2017: 14 · 2016: 7 · 2015: 16 · 2014: 4
FWCI
6.25
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • Harvard NeuroDiscovery Center
  • Ohio State University
  • Johns Hopkins University
  • Edward N. and Della L. Thome Memorial Foundation
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS064275, U01NS074601)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
GLT-1, glutamate transporters, translational activation, neuroprotection, excitotoxicity, amyotrophic lateral sclerosis, temporal lobe epilepsy, protein kinase C, YB-1, glutamate clearance, neurodegenerative diseases, lifespan extension
MeSH terms
Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Anterior Horn Cells, Astrocytes, Cell Line, Enzyme Activation, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Pilocarpine, Protein Kinase C, Pyridazines, Pyridines, Status Epilepticus, Superoxide Dismutase, Tissue Distribution, Transcription Factors, Protein Biosynthesis, Neuroprotective Agents, Coculture Techniques, Mutation, Missense, Excitatory Amino Acid Transporter 2, Mice, Rats

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