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. 2012 Sep;4(13):1689-700.
doi: 10.4155/fmc.12.122.

Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases

Chien-Liang Glenn Lin  1 , Qiongman Kong, Gregory D Cuny, Marcie A Glicksman
Affiliations

Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases

Chien-Liang Glenn Lin et al. Future Med Chem. 2012 Sep.

Abstract

Glutamate is the primary excitatory amino acid neurotransmitter in the CNS. The concentration of glutamate in the synaptic cleft is tightly controlled by interplay between glutamate release and glutamate clearance. Abnormal glutamate release and/or dysfunction of glutamate clearance can cause overstimulation of glutamate receptors and result in neuronal injury known as excitotoxicity. The glial glutamate transporter EAAT2 plays a major role in glutamate clearance. Dysfunction or reduced expression of EAAT2 has been documented in many neurodegenerative diseases. In addition, many studies in animal models of disease indicate that increased EAAT2 expression provides neuronal protection. Here, we summarize these studies and suggest that EAAT2 is a potential target for the prevention of excitotoxicity. EAAT2 can be upregulated by transcriptional or translational activation. We discuss current progress in the search for EAAT2 activators, which is a promising direction for the treatment of neurodegenerative diseases.

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Figures

Figure 1
Figure 1. Glutamatergic neurotransmission and excitotoxicity
(A) Under normal conditions, glutamate released from the presynaptic neuron activates ionotropic glutamate receptors (NMDA and AMPA receptors) present on the postsynaptic neuron. This results in the influx of Na+ and Ca2+ ions into the cell, leading to depolarization and generation of an action potential. (B) Acute elevations of glutamate (when the release of glutamate from presynaptic terminals and/or glial cells is increased) in conditions such as stroke, neurotrauma and epilepsy cause severe neuronal injury or death. (C) Chronic and mild elevations of glutamate (when the glutamate reuptake function is impaired) such as Alzheimer’s disease, Parkinson’s disease and amylotrophic lateral sclerosis cause neuronal damage. (D) Increased EAAT2 is a potential therapeutic strategy for the prevention of excitotoxicity. AMPA: α-amino-3-hydroxy-5-methyl-4 isoxazolepropionate; NMDA: N-methyl-D-aspartate.
Figure 2
Figure 2
Ceftriaxone and LDN-212320.
See this image and copyright information in PMC

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