Mechanism Behind Reduction of Neuronal Cell Death by Antibiotics Identified

Researchers from Virginia Commonwealth University have reported the discovery of a mechanism explaining how an antibiotic works to modulate the activity of a neurotransmitter that

The mechanism behind how antibiotics regulate the activity of a neurotransmitter has been found, researchers from Virginia Commonwealth University have revealed.

They believe that the finding may open up the possibility of developing new and improved 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. Over a period of time large number of neurons die or stop functioning.

The study led by Paul B. Fisher has uncovered the mechanism of action of ceftriaxone, a third-generation antibiotic with neuroprotective properties, in glutamate transport.

Glutamate is an amino acid that is important in nerve transmission and the synapse, a 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.

If glutamate is not cleared out of the synapse, neurons become damaged and die by a process called excitotoxicity.

"Glutamate excitotoxicity is a very important and fundamental process in neurodegeneration," said Fisher, 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,

"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," he added.

For the study, Fisher and his team examined 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, they studied all the regions and sequences in the promoter region and systematically eliminated them to then define which region was necessary to respond to ceftriaxone.

This directed 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.

The findings are published in the May 9 issue of the Journal of Biological Chemistry.

Source-ANI
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