β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Jeffrey D. Rothstein, Sarjubhai Patel, Melissa R. Regan, Christine Haenggeli, Yanhua H. Huang, Dwight E. Bergles, Lin Jin, Margaret Dykes Hoberg, Svetlana Vidensky, Dorothy S. Chung, Vang Toan Shuy, Lucie I. Bruijn, Zao Zhong Su, Pankaj Gupta, Paul B. Fisher

Research output: Contribution to journalArticle

Abstract

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 epilepsy 6. 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 GIT1 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 neurotoxicity1,9-11. 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.

Original languageEnglish (US)
Pages (from-to)73-77
Number of pages5
JournalNature
Volume433
Issue number7021
DOIs
StatePublished - Jan 6 2005

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    Rothstein, J. D., Patel, S., Regan, M. R., Haenggeli, C., Huang, Y. H., Bergles, D. E., Jin, L., Hoberg, M. D., Vidensky, S., Chung, D. S., Shuy, V. T., Bruijn, L. I., Su, Z. Z., Gupta, P., & Fisher, P. B. (2005). β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature, 433(7021), 73-77. https://doi.org/10.1038/nature03180