Glutamate-mediated excitotoxicity is believed to be involved in the pathogenesis of many neurological disorders. Under disease conditions, elevated extracellular glutamate concentrations can occur when the release from presynaptic terminals is augmented or when the reuptake from the synaptic cleft is insufficient. Excessive glutamate can cause over-stimulation of glutamate receptors and result in neuronal injury or death .. One way to prevent excitotoxicity is to block glutamate receptor;however, this approach is not very successful in human .. Another approach is enhanced glutamate reuptake .. The glial glutamate transporter EAA T2 is the major glutamate transporter in terminating synaptic transmission. One potential therapeutic approach to protect against excitotoxic neuron damage is to activate EAA T2 protein expression and boost glutamate reuptake .. By high-throughput screening, we have recently identified two classes of compounds which can specifically activate EAA T2 protein expression. The first objective is to optimize these compounds to increase their safety and efficacy The second aim of this project is to evaluate the biological activity of all analogues emerging from Aim 1 in cultured primary astrocytes as well as in wild-type mice ..
The third aim i s to identify signaling pathways involved in compound-induced EAAT2 expression .. Importantly, the proposal merges the experience and capabilities of the laboratories investigating the molecular biology/biochemistry of glutamate transporters with the expertise of a Center devoted to the development of novel therapies for neurodegenerative diseases. Our ultimate goal is to develop a new drug with remarkable therapeutic effect by inducing EAA T2 expression.

Public Health Relevance

Glutamate-mediated excitotoxicity is believed to be involved in the pathogenesis of many neurological disorders, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Inefficient glutamate uptake into the astrocytes that surround neuronal synapses is a major contributing factor of glutamate-mediated excitotoxicity. The glial glutamate transporter EAAT2 plays a major role in glutamate uptake. One potential therapeutic approach is the increase of EAAT2 protein expression. The goals of this project are 1) to identify safe and effective compounds which can stimulate translation of EAAT2 mRNA, 2) to preclinically test the compounds in the SOD1(G93A) transgenic mouse model for ALS as well as in the APPSw/Ind transgenic mouse model for Alzheimer's disease, 3) to characterize the molecular mechanisms underlying the translational regulation of EAAT2 expression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Gubitz, Amelie
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Ohio State University
Schools of Medicine
United States
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Takahashi, Kou; Foster, Joshua B; Lin, Chien-Liang Glenn (2015) Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cell Mol Life Sci 72:3489-506
Takahashi, Kou; Kong, Qiongman; Lin, Yuchen et al. (2015) Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease. J Exp Med 212:319-32
Kong, Qiongman; Chang, Ling-Chu; Takahashi, Kou et al. (2014) Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection. J Clin Invest 124:1255-67
Lin, Chien-Liang Glenn; Kong, Qiongman; Cuny, Gregory D et al. (2012) Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. Future Med Chem 4:1689-700
Kong, Qiongman; Takahashi, Kou; Schulte, Delanie et al. (2012) Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus. Neurobiol Dis 47:145-54
Kong, Qiongman; Carothers, Sarah; Chang, Yueming et al. (2012) The importance of preclinical trial timing - a potential reason for the disconnect between mouse studies and human clinical trials in ALS. CNS Neurosci Ther 18:791-3
Xing, Xuechao; Chang, Ling-Chu; Kong, Qiongman et al. (2011) Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators. Bioorg Med Chem Lett 21:5774-7
Tian, Guilian; Kong, Qiongman; Lai, Liching et al. (2010) Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer's disease. J Neurochem 113:978-89
Colton, Craig K; Kong, Qiongman; Lai, Liching et al. (2010) Identification of translational activators of glial glutamate transporter EAAT2 through cell-based high-throughput screening: an approach to prevent excitotoxicity. J Biomol Screen 15:653-62