title: 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.
authors.forename: Qiongman
authors.initials: Q
authors.lastname: Kong
authors.forename: Ling-Chu
authors.initials: LC
authors.lastname: Chang
authors.forename: Kou
authors.initials: K
authors.lastname: Takahashi
authors.forename: Qibing
authors.initials: Q
authors.lastname: Liu
authors.forename: Delanie A
authors.initials: DA
authors.lastname: Schulte
authors.forename: Liching
authors.initials: L
authors.lastname: Lai
authors.forename: Brian
authors.initials: B
authors.lastname: Ibabao
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Lin
authors.forename: Nathan
authors.initials: N
authors.lastname: Stouffer
authors.forename: Chitra
authors.initials: C
authors.lastname: Das Mukhopadhyay
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Seyb
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.forename: Chien-Liang Glenn
authors.initials: CL
authors.lastname: Lin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D004789:Enzyme Activation / Q000187:drug effects; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D020125:Mutation, Missense; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010862:Pilocarpine; D014176:Protein Biosynthesis / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D010862:Pilocarpine; D011493:Protein Kinase C; D011724:Pyridazines; D011725:Pyridines; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors; C588183:LDN-OSU-0212320; C541744:Ybx1 protein, mouse; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat