Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

• Published in: The Journal of clinical investigation 2014-03, Vol.124 (3), p.1255-1267
• Main Authors: Kong, Qiongman, Chang, Ling-Chu, Takahashi, Kou, Liu, Qibing, Schulte, Delanie A, Lai, Liching, Ibabao, Brian, Lin, Yuchen, Stouffer, Nathan, Das Mukhopadhyay, Chitra, Xing, Xuechao, Seyb, Kathleen I, Cuny, Gregory D, Glicksman, Marcie A, Lin, Chien-Liang Glenn
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - pathology; Animals; Anterior Horn Cells - drug effects; Astrocytes - drug effects; Astrocytes - metabolism; Biomedical research; Biotechnology; Carrier proteins; Cell Line; Chronic illnesses; Coculture Techniques; Degeneration; Enzyme Activation - drug effects; Excitatory Amino Acid Transporter 2 - genetics; Excitatory Amino Acid Transporter 2 - metabolism; Female; Genetic research; Genetic translation; Identification and classification; Kinases; Laboratory animals; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity - drug effects; Mutation, Missense; Nervous system; Neurons; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Pilocarpine; Primaries & caucuses; Properties; Protein Biosynthesis - drug effects; Protein Kinase C - metabolism; Proteins; Pyridazines - pharmacokinetics; Pyridazines - pharmacology; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Rodents; Status Epilepticus - chemically induced; Status Epilepticus - drug therapy; Status Epilepticus - pathology; Studies; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Survival analysis; Tissue Distribution; Transcription Factors - metabolism; Transgenic animals
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci66163

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.