Glutamate Inhibitors Protect Against Nerve Damage in Huntington's

Researchers working with mouse brain cells growing in tissue culture have found evidence that supports the potential use of the glutamate pathway inhibitors memantine and riluzole for treatment of Huntington's disease (HD).

Glutamate is the most abundant fast, excitatory neurotransmitter in the mammalian nervous system. At chemical synapses, glutamate is stored in vesicles until nerve impulses trigger its release from the pre-synaptic cell. In the opposing post-synaptic cell, glutamate receptors, such as the NMDA receptor, bind glutamate and are activated. Because of its role in synaptic plasticity, it is believed that glutamate is involved in cognitive functions such as learning and memory in the brain.

HD affects the brain striatum, which is involved in the control of movement and of "executive function,” or planning and abstract thinking. It primarily attacks the striatal medium spiny neurons, the main component of the striatum. Previous research had shown that dysregulation of the glutamate/calcium signaling pathway was a possible cause of striatal neurodegeneration in HD.

In the current study, investigators at the University of Texas Southwestern Medical Center (Dallas, USA) worked with cultured mouse striatal spiny neurons to determine the capability of five clinically relevant glutamate pathway inhibitors to protect against damage caused by HD.

Results published in the October 30, 2006, issue of Neuroscience Letters revealed that folic acid, gabapentin, and lamotrigine did not protect HD neurons from glutamate-induced cell death, but memantine and riluzole were protective. These findings were interpreted as supporting the potential use of memantine and riluzole for treatment of HD.

"We systematically and quantititatively tested the clinically relevant drugs side-by-side in the same HD model. That has never been done before,” said senior author Dr. Ilya Bezprozvanny, associate professor of physiology at the University of Texas Southwestern Medical Center. "Our results provide the first systematic comparison of various clinically relevant glutamate pathway inhibitors for HD treatment and indicate that memantine holds the most promise based on its in vitro efficacy. Whole animal studies of memantine in an HD mouse model will be required to validate these findings.”



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University of Texas Southwestern Medical Center