Antibiotic Protects Nerves By Removing Excess Glutamate

[LNN]

I came across this while researching glutamate

 

http://www.ninds.nih.gov/news_and_events/news_articles/news_article_ALS_ceftriaxone.htm

 

What's Old is New Again - Antibiotic Protects Nerves By Removing Excess Glutamate

 

For release: Monday, February 07, 2005

 

A new study shows that a common antibiotic used to treat bacterial infections increases survival rates and delays nerve damage in a mouse model for amyotrophic lateral sclerosis (ALS). The antibiotic works by activating or "turning on" the gene encoding the glutamate transporter in neurons. This finding may lead to new drug treatments for ALS and other neurodegenerative diseases.

 

Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins University in Baltimore, Maryland , and his colleagues reported the beneficial effects of the antibiotic ceftriaxone in a mouse animal model of ALS in the January 6, 2005, issue of Nature.* Ceftriaxone treatment, started at the onset of the disease in the mouse model, delayed the loss of neurons and muscle strength while increasing survival time. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

 

The initial focus on antibiotics for ALS resulted from the NINDS-led Drug Screening Consortium, an effort in which 27 investigators, including Dr. Rothstein, screened 1040 existing drugs to assess their potential to treat a variety of neurodegenerative disorders. Co-sponsored by The ALS Association and two Huntington's disease groups, the purpose of this cooperative drug screening approach was to use rapid technology to find new uses for existing drugs. Ceftriaxone was one of the drugs that showed promise for ‘crossing-over' into neurodegenerative diseases.

 

The potentially therapeutic properties of ceftriaxone for ALS have little to do with its antibiotic effects but instead result from its ability to increase the number of glutamate transporters. Glutamate transporters are proteins that vacuum up the excitatory neurotransmitter glutamate. Normally, glutamate acts to excite nerves so that electrical signals can travel from one to the next. Too much glutamate has a toxic effect on nerve cells and has been implicated in neurodegenerative diseases such as ALS, Huntington's disease, Alzheimer's disease, epilepsy and stroke. Removing glutamate through the transporter prevents nerve damage caused by excessive amounts of glutamate. "Increasing the glutamate transporter expression and removing the excess glutamate is essentially like turning on a fan to clear a smoke-filled room," says Dr. Rothstein.

 

As part of the Drug Screening Consortium, Dr. Rothstein found that 15 drugs from the penicillin family, named beta lactams, increased glutamate transport in cultures of spinal cord slices and therefore increased removal of this excitatory neurotransmitter. Because this class of antibiotics can increase removal of excess glutamate, researchers hypothesized this could lead to better drug treatment therapies for neurodegenerative disorders like ALS.

 

"We're very excited by these drugs' abilities," says Dr. Rothstein. "These studies show for the first time that drugs, not just genetic engineering, can increase the numbers of specific transporters in brain cells. Because we study ALS, we tested the drugs in a mouse model of that disease, but this approach could be valuable to other conditions. It has potential applications in numerous neurologic and psychiatric conditions that arise from abnormal control of glutamate."

 

As a result of these recent findings, the NINDS will fund a multi-center clinical trial in ALS patients that is slated to start in spring 2005. The placebo-controlled clinical trial will determine the safety and efficacy of long-term ceftriaxone treatment in patients with ALS. "The discovery of new uses for antibiotics in ALS validates the drug screening approach as a rapid and effective method of finding new uses for existing drugs," says Jill Heemskerk, Ph.D., NINDS' program director for the screening program. "There are currently no effective drugs for these diseases, and the study of compounds identified by this approach will provide desperately needed inroads into this uncharted territory," added Dr. Heemskerk.

 

ALS and other neurodegenerative diseases are currently poorly understood, lack successful treatments and cause progressive disability in affected patients. Dr. Rothstein and others in the field believe that having the ability to selectively target the glutamate transporter will be a powerful tool not only for treating neurodegenerative diseases but also for developing an important new class of drugs. Since long-term antibiotic treatment could lead to antibiotic resistance or toxic side-effects, researchers are working to develop novel, less toxic drugs that are more selective in removing excess levels of glutamate. Future research will also test other beta-lactam antibiotics that may be more effective. If successful, these drugs will shed new light on treatments for neurodegenerative disorders and help to prevent nerve damage and death in patients.

 

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.

 

References:

 

*Rothstein JD, Patel S, Regan MR, Haenggel C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Vang Toan S, Bruijn LI, Su Z-Z, Gupta P, Fisher PB. "b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression." Nature, January 6, 2005, Vol. 433, pp.73-77.

 

**Miller TM, Cleveland DW. "Treating neurodegenerative disease with antibiotics." Science, January 21, 2005, Vol. 307, pp. 361-362.

 

By Michelle D. Jones-London, Ph.D.

[Iowadawn]

One of the drugs my PANDAS son is on, and is now given to some autistic kids, is the drug Namenda. It is a glutamate antagonist. It has been the one drug I have been quite pleased with. Our hope is to get him off of everything--that is our psychiatrist's expectation as well. Namenda is an Alzheimer's drug.

 

Dawn

[MomWithOCDSon]

The drug that is currently undergoing trial for OCD at NIMH . . . Riluzole . . . is also a glutamate agonist, FDA approved for ALS. The social worker running the trial with Dr. Grant has told me that preliminary results have been very good.

 

Interestingly, though, to enter the trial, you have to discontinue use of NAC (n-acetylcystein), which is also supposed to help modulate glutamate in the brain. NAC is available over-the-counter, and many families with OCD enjoy positive results with it.

[Iowadawn]

Child psychiatrists in our area of the country have been using it with good success for about 5 years and few (known) side effects. The positive reports of its use off label is probable what would prompt a trial like Riluzole. I'll still be glad when he's off it.

[trggirl]

You may be on to something there especially considering that CamK increases Norepineprine and Glutamate. Very interesting. Thanks for sharing.

[Fixit]

I came across this while researching glutamate

 

http://www.ninds.nih.gov/news_and_events/news_articles/news_article_ALS_ceftriaxone.htm

 

What's Old is New Again - Antibiotic Protects Nerves By Removing Excess Glutamate

 

For release: Monday, February 07, 2005

 

A new study shows that a common antibiotic used to treat bacterial infections increases survival rates and delays nerve damage in a mouse model for amyotrophic lateral sclerosis (ALS). The antibiotic works by activating or "turning on" the gene encoding the glutamate transporter in neurons. This finding may lead to new drug treatments for ALS and other neurodegenerative diseases.

 

Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins University in Baltimore, Maryland , and his colleagues reported the beneficial effects of the antibiotic ceftriaxone in a mouse animal model of ALS in the January 6, 2005, issue of Nature.* Ceftriaxone treatment, started at the onset of the disease in the mouse model, delayed the loss of neurons and muscle strength while increasing survival time. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

 

The initial focus on antibiotics for ALS resulted from the NINDS-led Drug Screening Consortium, an effort in which 27 investigators, including Dr. Rothstein, screened 1040 existing drugs to assess their potential to treat a variety of neurodegenerative disorders. Co-sponsored by The ALS Association and two Huntington's disease groups, the purpose of this cooperative drug screening approach was to use rapid technology to find new uses for existing drugs. Ceftriaxone was one of the drugs that showed promise for ‘crossing-over' into neurodegenerative diseases.

 

The potentially therapeutic properties of ceftriaxone for ALS have little to do with its antibiotic effects but instead result from its ability to increase the number of glutamate transporters. Glutamate transporters are proteins that vacuum up the excitatory neurotransmitter glutamate. Normally, glutamate acts to excite nerves so that electrical signals can travel from one to the next. Too much glutamate has a toxic effect on nerve cells and has been implicated in neurodegenerative diseases such as ALS, Huntington's disease, Alzheimer's disease, epilepsy and stroke. Removing glutamate through the transporter prevents nerve damage caused by excessive amounts of glutamate. "Increasing the glutamate transporter expression and removing the excess glutamate is essentially like turning on a fan to clear a smoke-filled room," says Dr. Rothstein.

 

As part of the Drug Screening Consortium, Dr. Rothstein found that 15 drugs from the penicillin family, named beta lactams, increased glutamate transport in cultures of spinal cord slices and therefore increased removal of this excitatory neurotransmitter. Because this class of antibiotics can increase removal of excess glutamate, researchers hypothesized this could lead to better drug treatment therapies for neurodegenerative disorders like ALS.

 

"We're very excited by these drugs' abilities," says Dr. Rothstein. "These studies show for the first time that drugs, not just genetic engineering, can increase the numbers of specific transporters in brain cells. Because we study ALS, we tested the drugs in a mouse model of that disease, but this approach could be valuable to other conditions. It has potential applications in numerous neurologic and psychiatric conditions that arise from abnormal control of glutamate."

 

As a result of these recent findings, the NINDS will fund a multi-center clinical trial in ALS patients that is slated to start in spring 2005. The placebo-controlled clinical trial will determine the safety and efficacy of long-term ceftriaxone treatment in patients with ALS. "The discovery of new uses for antibiotics in ALS validates the drug screening approach as a rapid and effective method of finding new uses for existing drugs," says Jill Heemskerk, Ph.D., NINDS' program director for the screening program. "There are currently no effective drugs for these diseases, and the study of compounds identified by this approach will provide desperately needed inroads into this uncharted territory," added Dr. Heemskerk.

 

ALS and other neurodegenerative diseases are currently poorly understood, lack successful treatments and cause progressive disability in affected patients. Dr. Rothstein and others in the field believe that having the ability to selectively target the glutamate transporter will be a powerful tool not only for treating neurodegenerative diseases but also for developing an important new class of drugs. Since long-term antibiotic treatment could lead to antibiotic resistance or toxic side-effects, researchers are working to develop novel, less toxic drugs that are more selective in removing excess levels of glutamate. Future research will also test other beta-lactam antibiotics that may be more effective. If successful, these drugs will shed new light on treatments for neurodegenerative disorders and help to prevent nerve damage and death in patients.

 

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.

 

References:

 

*Rothstein JD, Patel S, Regan MR, Haenggel C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Vang Toan S, Bruijn LI, Su Z-Z, Gupta P, Fisher PB. "b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression." Nature, January 6, 2005, Vol. 433, pp.73-77.

 

**Miller TM, Cleveland DW. "Treating neurodegenerative disease with antibiotics." Science, January 21, 2005, Vol. 307, pp. 361-362.

 

By Michelle D. Jones-London, Ph.D.

 

a little off topic...i see talk of agonist ant antagonist....

dob b said dopamine 1 was agonist and dopamine 2 antagonist...

can anyone explain the difference??

[trggirl]

A dopamine agonist means an agent that activates dopamine. A dopamine antagonist means an agent that blocks or works against dopamine.

Edited August 15, 2010 by Trg girl

[Rachel]

I am learning so much from this fourm. I keep digging and learning more. This post was very helpful. I thought that someone else might want to read it.

[qannie47]

Interesting....yes, so much to learn from this think tank

[qannie47]

Ceftriaxone

Potential neuroprotective antibiotic ceftriaxone reduced functional decline more than 30% according to phase II double-blind placebo-controlled study results presented by Massachusetts General Hospital’s Merit Cudkowicz MD MSc. The drug was subsequently withdrawn in August of 2012 due to insufficient efficacy at the phase III stage. 513 people with ALS participated.

The results raise key questions about enrollment, the number of people with ALS needed to participate and study duration – particularly to inform and empower phase II go/no go decisions

[3bmom]

Thank you to whomever bumped this info up. All these threads give you lots to think about. We could have a seminar based just on glutamate!

 

We are on prophylactic antibiotics and I always wondered after strep and myco are eliminated or reduced is the antibiotic doing something good we don't know about. I thought maybe holding an abundance of bad bacteria at bay but maybe it is glutamate or both.

[Dedee]

This is the generic name for Rocephin which is used to treat many Lyme patients including my son and daughter. It has worked well for us. After reading this, I suspect it could be the GABA / Glutamate issue that could be in play. My daughter has always had issues with high glutamate.

 

Dedee