Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

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 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Screen of 1,040 FDA-approved drugs reveals β-lactam antibiotics as inducers of GLT1 protein expression.
Figure 2: Promoter reporter analysis. β-Lactams activate human GLT1 promoter.
Figure 3: β-Lactam induces transporter promoter activation and protein expression in vivo.
Figure 4: In vitro and in vivo neuroprotection by ceftriaxone.

Similar content being viewed by others

References

  1. Rothstein, J. D. et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16, 675–686 (1996)

    Article  CAS  Google Scholar 

  2. Danbolt, N. C. Glutamate uptake. Prog. Neurobiol. 65, 1–105 (2001)

    Article  CAS  Google Scholar 

  3. Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J. & Kuncl, R. W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995)

    Article  CAS  Google Scholar 

  4. Rao, V. L. et al. Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain. J. Neurosci. 21, 1876–1883 (2001)

    Article  CAS  Google Scholar 

  5. Ye, Z. C., Rothstein, J. D. & Sontheimer, H. Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. J. Neurosci. 19, 10767–10777 (1999)

    Article  CAS  Google Scholar 

  6. Sepkuty, J. P. et al. A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. J. Neurosci. 22, 6372–6379 (2002)

    Article  CAS  Google Scholar 

  7. Su, Z. Z. et al. Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2). Proc. Natl Acad. Sci. USA 100, 1955–1960 (2003)

    Article  ADS  CAS  Google Scholar 

  8. Goodman, L. S., Hardman, J. G., Limbird, L. E. & Gilman, A. G. Goodman & Gilman's The Pharmacological Basis of Therapeutics (McGraw-Hill Medical Pub. Division, New York, 2001)

    Google Scholar 

  9. Tanaka, K. et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276, 1699–1702 (1997)

    Article  CAS  Google Scholar 

  10. Watase, K. et al. Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur. J. Neurosci. 10, 976–988 (1998)

    Article  CAS  Google Scholar 

  11. Rothstein, J. D., Jin, L., Dykes-Hoberg, M. & Kuncl, R. W. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc. Natl Acad. Sci. USA 90, 6591–6595 (1993)

    Article  ADS  CAS  Google Scholar 

  12. Chandrasekar, P., Rolston, K., Smith, B. & LeFrock, J. Diffusion of ceftriaxone into the cerebrospinal fluid of adults. J. Antimicrob. Chemother. 14, 427–430 (1984)

    Article  CAS  Google Scholar 

  13. Nau, R. et al. Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges. Antimicrob. Agents Chemother. 37, 1518–1524 (1993)

    Article  CAS  Google Scholar 

  14. Kazragis, R., Dever, L., Jorgensen, J. & Barbour, A. In vivo activities of ceftriaxone and vancomycin against Borrelia spp. in the mouse brain and other sites. Antimicrob. Agents Chemother. 38, 2632–2636 (1996)

    Article  Google Scholar 

  15. Chen, W. et al. Expression of a variant form of the glutamate transporter GLT1 in neuronal cultures and in neurons and astrocytes in the rat brain. J. Neurosci. 22, 2142–2152 (2002)

    Article  CAS  Google Scholar 

  16. Schlag, B. D. et al. Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol. Pharmacol. 53, 355–369 (1998)

    Article  CAS  Google Scholar 

  17. Guo, H. et al. Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum. Mol. Genet. 12, 2519–2532 (2003)

    Article  CAS  Google Scholar 

  18. Romera, C. et al. In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-alpha pathway. J. Neurosci. 24, 1350–1357 (2004)

    Article  CAS  Google Scholar 

  19. Spalloni, A. et al. Cu/Zn-superoxide dismutase (GLY93 → ALA) mutation alters AMPA receptor subunit expression and function and potentiates kainate-mediated toxicity in motor neurons in culture. Neurobiol. Dis. 15, 340–350 (2004)

    Article  CAS  Google Scholar 

  20. Canton, T. et al. RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. J. Pharmacol. Exp. Ther. 299, 314–322 (2001)

    CAS  PubMed  Google Scholar 

  21. Rothstein, J. D. & Kuncl, R. W. Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. J. Neurochem. 65, 643–651 (1995)

    Article  CAS  Google Scholar 

  22. Kaspar, B. K., Llado, J., Sherkat, N., Rothstein, J. D. & Gage, F. H. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301, 839–842 (2003)

    Article  ADS  CAS  Google Scholar 

  23. Drachman, D. B. et al. Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann. Neurol. 52, 771–778 (2002)

    Article  CAS  Google Scholar 

  24. Howland, D. S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl Acad. Sci. USA 99, 1604–1609 (2002)

    Article  ADS  CAS  Google Scholar 

  25. Rothstein, J. D., Martin, L. J. & Kuncl, R. W. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N. Engl. J. Med. 326, 1464–1468 (1992)

    Article  CAS  Google Scholar 

  26. Gong, S., Yang, X. W., Li, C. & Heintz, N. Highly efficient modification of bacterial artificial chromosomes (BACs) using novel shuttle vectors containing the R6Kgamma origin of replication. Genome Res. 12, 1992–1998 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeffrey D. Rothstein.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Data and additional references. (DOC 66 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rothstein, J., Patel, S., Regan, M. et al. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005). https://doi.org/10.1038/nature03180

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03180

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing