Antibiotic for neuroprotection

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Antibiotic for neuroprotection

Postby TwistedHelix » Sun May 11, 2008 6:49 am

Although this article doesn't directly mention MS, neurodegeneration is certainly a component of the disease process so anything which helps can only be…erm… helpful:
Researchers uncover mechanism of action of antibiotic able to reduce neuronal cell death in brain

Research Highlights:

* Mechanism of action of compound found to induce neurotransmitter activity in brain cells

* The findings may lead researchers to develop potential novel therapies to treat Alzheimer's disease, amyotrophic lateral sclerosis, Huntington’s disease, epilepsy, stroke/ischemia, dementia and malignant gliomas

RICHMOND, Va. (May 9, 2008) – Virginia Commonwealth University researchers have discovered how an antibiotic works to modulate the activity of a neurotransmitter that regulates brain functions, which eventually could lead to therapies to treat Alzheimer’s disease, Huntington’s disease, epilepsy, stroke, dementia and malignant gliomas.

Neurodegenerative diseases are caused by the deterioration of neurons in the brain and spine resulting in problems related to either movement or memory. For most patients, it may be months or years before symptoms are evident because a large number of neurons die or stop functioning over a period of time. Currently, there are few treatment options for stopping this degeneration, and those currently being evaluated have shown minimal or no beneficial activity.

Paul B. Fisher, M.Ph., Ph.D., a professor and interim chair of the Department of Human and Molecular Genetics, and director of the VCU Institute of Molecular Medicine, in the VCU School of Medicine, and colleagues recently reported on the mechanism of action of ceftriaxone, a third-generation antibiotic with neuroprotective properties, in glutamate transport. The findings, published in the May 9 issue of the Journal of Biological Chemistry, suggest that this antibiotic or a similar drug may serve as a potential therapy against neurodegenerative disease caused by glutamate toxicity.

Glutamate is an amino acid that is important in nerve transmission and the synapse - the region that connects one neuron to another in the brain. When an excess of glutamate collects in the synapse, the result is glutamate toxicity or excitotoxicity. Ultimately, if glutamate is not cleared out of the synapse, neurons become damaged and die by a process called excitotoxicity. In previous studies, Fisher’s team identified ceftriaxone as a potent physiological stimulator of glutamate transport both in cell culture and in animal models.

“Glutamate excitotoxicity is a very important and fundamental process in neurodegeneration,” said Fisher. “Finding molecules, such as ceftriaxone, that may correct this problem can lead to preservation and increased survival of neurons in the brain and it may have direct implications in the therapy of many neurodegenerative diseases, such as in Alzheimer’s disease, stroke, ALS and epilepsy.”

In this study, Fisher and his colleagues were interested in identifying how the promoter region of the EAAT2 gene controlled the expression of glutamate in a group of brain cells called astrocytes. Using molecular biological approaches, the team examined all the regions and sequences in the promoter region and systematically eliminated them to then define which region was necessary to respond to ceftriaxone.

According to Fisher, this led the team to a critical transcription factor called nuclear factor kappaB, NF- kappaB, which regulates many functions in the brain and other parts of the body. This is a central molecule involved in regulation of genes controlling cell growth and survival. Once they identified critical regions in the EAAT2 promoter that might regulate activity, they found that alteration of one specific NF-kappaB site by mutation in the promoter was responsible for up-regulation of EAAT2 expression and consequently glutamate transport by ceftriaxone.

“This work not only has implications for the field of neurodegeneration and neurobiology, but may also help us more clearly understand brain cancer, including malignant glioma, an invariably fatal tumor, and how it impacts brain function,” said Fisher, who is the first incumbent of the Thelma Newmeyer Corman Endowed Chair in Cancer Research and researcher with the VCU Massey Cancer Center.

Future studies will examine ways to modify the structure of ceftriaxone through medicinal chemistry to create molecules that are pharmacologically improved. Currently, ceftriaxone needs to be injected, which is not the ideal for patient therapy, however, the development of an oral form would be a more preferential way to treat patients.

###

This work was supported by a program project grant from the National Institutes of Health, Neurology and Stroke, and the Samuel Waxman Cancer Research Foundation.

Fisher worked with a team that included: Seok-Geun Lee, Ph.D., lead author of the paper and assistant professor, and Zaozhong Su, Ph.D., associate professor, both in the VCU Department of Human and Molecular Genetics; Devanand Sarkar, MBBS, Ph.D., assistant professor and Harrison Endowed Scholar in Cancer Research at the VCU Massey Cancer Center and Department of Human and Molecular Genetics; and David J. Volsky, Ph.D., professor, St. Luke’s Roosevelt Hospital Center, Columbia University in New York.

About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls nearly 32,000 students in 205 certificate and degree programs in the arts, sciences and humanities. Sixty-five of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.
Dom
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Postby rainer » Sun May 11, 2008 1:27 pm

Nice one. Thanks.
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Postby cheerleader » Sun May 11, 2008 8:05 pm

Thanks, Dom.
Ceftriaxone is prescribed as Rocephin. This is the antibiotic given intravenously for Lyme disease, spirochete infections, as well as gonorrhea.

Wonder if other oral antibiotics also provide glutamate transport? This might explain the neuroprotective properties of minocycline and doxy, which have not really been explained.

interesting,
AC
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dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Minocycline and Neuroprotection

Postby Shayk » Wed May 14, 2008 8:23 pm

Dom

Thanks for posting this....the researchers are right in my backyard--maybe I need to clue them in to add MS to their list of neurodegenerative disorders. :wink:

AC

The question about abx and glutamate transport is a good one. At a minimum, minocycline does seem to impact glutamate toxicity.

Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons
This pharmacological profile suggests that the neuroprotective effects of minocycline might be associated with the mitigation of neuronal excitability, glutamate release, and Ca(2+) overloading.


Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia
Glutamate excitotoxicity to a large extent is mediated through activation of the N-methyl-D-aspartate (NMDA)-gated ion channels in several neurodegenerative diseases and ischemic stroke.

Minocycline inhibited all these responses to NMDA.


And, for anyone interested, the following article is available free through the end of May via Sage Publications (also publish the MS Journal).Minocycline as a Neuroprotective Agent

So sorry your husband had such a migraine after he started the mino.

Take care everyone

Sharon
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Postby DIM » Wed May 14, 2008 11:41 pm

Quite interesting Ceftriaxone (Rocephin) is recommended for Lyme, sexually trasmitted diseases, gallstones, chlamydia, herpes etc most of them connected with MS!
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Postby cheerleader » Thu May 15, 2008 8:12 am

Thanks for the info on glutamate release, Sharon. Think you need to head over to the Commonwealth University offices and make a case for MS research!

Jeff went from 100 to 200mg. of mino, and that's when the monster headache showed up. We're talking to his neuro about continuing the treatment at a lower dosage. He was fine on 100 mg. for three weeks. I really want to keep up the neuroprotective actions, maybe 50 mg. daily. We'll see. I'm wondering if the glutamate transport might have contributed to the intracranial pressure.
http://www.medsafe.govt.nz/profs/PUarticles/bih.htm

Dim, I thought the same thing when I saw the list for rocephin...all spirochetal infections implicated in MS. Don't think it's a coincidence!

interesting,
AC
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Postby Shayk » Thu May 15, 2008 7:39 pm

AC

Unfortunately VCU doesn't have an MS Center. If it did, I'd be on their case for sure for a Phase II DHEA trial in MS. They did one of the Phase I studies.

Besides neuroprotection, DHEA is a powerful immune modulator, opposes cortisol , and protects against some viruses/bacteria too, at least in mice.

Excellent research you've done there...glad mino isn't totally ruled out yet.

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