Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS)3, stroke4, brain tumours5 and epilepsy6. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many β-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene7. β-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways8. When delivered to animals, the β-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity1,9,10,11. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity11. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.
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Under a licensing agreement between Ruxton Pharmaceuticals, Inc. and the Johns Hopkins University, J.D.R. is entitled to a share of royalty received by the University on sales of products described in this study. J.D.R. and the University own Ruxton Pharmaceuticals, Inc. stock, which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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We are grateful to J. Lee and C. Cocci for technical assistance; K. Tanaka for GLT1-null mice; C. Leahy for ALS mouse studies; and J. Heemskerk for initiating the project, discussions and encouragement. G93A SOD1 mice were provided by Project ALS. The work was supported by the NIH, the Muscular Dystrophy Association and The Robert Packard Center for ALS Research at Johns Hopkins.
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