Full text of NEJM and Nature refs on lactams and glutamate trnspt.

[Guest guest]

I have the full text of the New England Journal of Medicine piece (I

subscribed as a student for $49). I am not comfortable posting

proprietary material, but will email the text on request. It is

mostly editorial comment, anyhow.

I believe that I & I should apply for group acces - we really have a

good case for having access to this kind of information.

The NEJM article is cross referenced to the following letter to

Nature, which appears to be the main published source for this data.

Letters to Nature

Nature 433, 73-77 (6 January 2005) | 10.1038/nature03180

-Lactam antibiotics offer neuroprotection by increasing glutamate

transporter expression

D. Rothstein1,2, Sarjubhai Patel1, R. Regan1,

Haenggeli1, Yanhua H. Huang2, Dwight E. Bergles2, Lin

Jin1, Margaret Dykes Hoberg1, Svetlana Vidensky1, Dorothy S. Chung1,

Shuy Vang Toan1, Lucie I. Bruijn3, Zao-zhong Su4, Pankaj Gupta4 and

B. Fisher4

Top of pageGlutamate 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 -lactam antibiotics are potent stimulators

of GLT1 expression. Furthermore, this action appears to be mediated

through increased transcription of the GLT1 gene7. -Lactams and

various semi-synthetic derivatives are potent antibiotics that act

to inhibit bacterial synthetic pathways8. W

hen delivered to animals, the -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.

Top of pageDepartment of Neurology,

Department of Neuroscience, s Hopkins University, Baltimore,

land 21287, USA

The ALS Association, Palm Harbor, Florida 34685, USA

Columbia University Medical Center, College of Physicians and

Surgeons, Department of Pathology, Neurosurgery and Urology, New

York, New York 10032, USA

Correspondence to: D. Rothstein1,2 Correspondence and

requests for materials should be addressed to J.D.R. ( Email:

jrothste@...).

Received 11 July 2004; Accepted 4 November 2004

> >

> > Can you give the name of the NEJM article that is the source of

> this

> > quote. I couldn't reach it from the link, but have access to

hard

> > copies from the med school library, and would like to see the

> article.

> >

> > Again, they said, " ...there are anecdotal claims that chronic

> > fatigue syndromes respond to ceftriaxone (or other antibiotics)

> > because the underlying problem is chronic Lyme disease.

> > However, the study by Rothstein and colleagues1 indicates

> that

> > ceftriaxone may exert important effects on the central nervous

> > system that are independent of its role as an antibiotic. "

> >

> > Thank you.

> >