Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.
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.
Rothstein
Jeffrey D
JD
Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287, USA. jrothste@jhmi.edu
Patel
Sarjubhai
S
Regan
Melissa R
MR
Haenggeli
Christine
C
Huang
Yanhua H
YH
Bergles
Dwight E
DE
Jin
Lin
L
Dykes Hoberg
Margaret
M
Vidensky
Svetlana
S
Chung
Dorothy S
DS
Toan
Shuy Vang
SV
Bruijn
Lucie I
LI
Su
Zao-Zhong
ZZ
Gupta
Pankaj
P
Fisher
Paul B
PB
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002443:Ceftriaxone / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010406:Penicillins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014481:United States; D014486:United States Food and Drug Administration; D047090:beta-Lactams / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D010406:Penicillins; D012333:RNA, Messenger; D047090:beta-Lactams; D002443:Ceftriaxone