Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

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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Citation

Copyright 2014 Journal of Clinical Investigation. Recommended citation: Kong, Qiongman, Ling-Chu Chang, Kou Takahashi, Qibing Liu, Delanie A. Schulte, Liching Lai, Brian Ibabao et al. "Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection." The Journal of clinical investigation 124, no. 3 (2014): 1255-1267. doi:10.1172/JCI66163.URL: https://www.jci.org/articles/view/66163. Reproduced in accordance with the original publisher's licensing terms and with permission from the authors.