Cited by 1,518Neuroscience and Neuropharmacology ResearchAmino Acid Enzymes and MetabolismNeuroprotection in Cerebral Ischemia

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β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Rothstein, Jeffrey D., Patel, Sarjubhai, Regan, Melissa R., Haenggeli, Christine, Huang, Yanhua H., Bergles, Dwight E., Jin, Lin, Dykes Hoberg, Margaret, Vidensky, Svetlana, Chung, Dorothy S., Toan, Shuy Vang, Bruijn, Lucie I., Su, Zao-zhong, Gupta, Pankaj, Fisher, Paul B.·2005·Nature

DOI 10.1038/nature03180

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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), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. 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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Authors: Rothstein, J. D., Patel, S., Regan, M. R., Haenggeli, C., Huang, Y. H., Bergles, D. E., Jin, L., Dykes Hoberg, M., Vidensky, S., Chung, D. S., Toan, S. V., Bruijn, L. I., Su, Z.-Z., Gupta, P., & Fisher, P. B.
Affiliations: Johns Hopkins University (US)
Amyotrophic Lateral Sclerosis Association (US)
Columbia University Irving Medical Center (US)
Corresponding author: Rothstein, Jeffrey D.
ORCID: Rothstein, Jeffrey D.
Huang, Yanhua H.
Bergles, Dwight E.
Gupta, Pankaj
Fisher, Paul B.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-01
Volume: 433
Issue: 7021
Pages: 73-77
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03180
OpenAlex: W2083204774
Cited by: 1,518
References: 27
Citations by year: 2026: 49 · 2025: 52 · 2024: 47 · 2023: 48 · 2022: 53 · 2021: 55 · 2020: 60 · 2019: 56 · 2018: 52 · 2017: 76 · 2016: 85 · 2015: 84 · 2014: 107 · 2013: 96 · 2012: 98
FWCI: 31.20
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Muscular Dystrophy Association
Johns Hopkins University
Robert Packard Center for ALS Research, Johns Hopkins University
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
Keywords: beta-lactam antibiotics, ceftriaxone, penicillin, GLT-1, glutamate transporters, neuroprotection, glutamate excitotoxicity, amyotrophic lateral sclerosis, ischemic brain injury, motor neuron degeneration, drug repurposing, transcriptional activation, astrocytes
MeSH terms: Animals, Anti-Bacterial Agents, Ceftriaxone, Cell Count, Cells, Cultured, Central Nervous System, Drug Evaluation, Preclinical, Gene Expression Regulation, Mice, Transgenic, Motor Neurons, Penicillins, Promoter Regions, Genetic, RNA, Messenger, United States, United States Food and Drug Administration, Transcriptional Activation, Genes, Reporter, Neuroprotective Agents, Ischemic Preconditioning, Excitatory Amino Acid Transporter 2, beta-Lactams, Mice, In Vitro Techniques

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β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

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