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.