Dimebon

A known anti-histamine shows promise in preventing glutamate excitotoxicity and preserving normal levels of acetylcholine.

Glutamate excitotoxicity

The chemical glutamate is a normal excitatory neurotransmitter which means it is a routine part of nerve impulse transmission. When present in excessive amounts though, glutamate can cause a chain of reactions that ultimately leads to nerve cell death. This process is called "excitotoxicity" because glutamate over-excites the nerve cell and becomes bad for it, or toxic. Cell death can also occur at normal glutamate levels if nerve cells become "hypersensitive" to glutamate. Such hypersensitivity is thought to be the reason glutamate excitotoxicity exists with HD. For a more detailed explanation of this process, please see Glutamate Toxicity: Disease Mechanism V.

In rat studies, Dimebon has been shown to work against glutamate excitotoxicity in two main ways. First, Dimebon acts as an antagonist to glutamate by binding to its receptors, called NMDA receptors, on the surface of the nerve cells. If glutamate can't bind to the NMDA receptors because Dimebon is in the way, then glutamate cannot send its message to the cell. This process is similar to the situation that would arise if you needed to send an e-mail, but someone was sitting in your chair. If they sit there and don't send a message, and you can't sit down to send a message, then no message gets sent at all. This activity could prevent cell death whether there are abnormally high levels of glutamate in the brain or, as is most likely in Huntington's, nerve cells are hypersensitive to normal levels of glutamate.

Dimebon also counters excitotoxicity by blocking calcium ion (Ca2+) channels located within the external surface of nerve cells. This activity prevents the influx of Ca2+ ions that would otherwise result from hypersensitivity to glutamate. (For more information about this process please see Glutamate Toxicity: Disease Mechanism V.) When blocked, Ca2+ cannot get into the cell to activate free radicals and other damaging molecules that ultimately lead to cell death. In this way, Dimebon may be able to stop a cell from progressing towards cell death even if glutamate is able to over-excite it.

So Dimebon may help prevent nerve cell death by preventing glutamate from over-stimulating nerve cells and preventing over-excited cells from taking in large amounts of Ca2+. How else might Dimebon help treat HD?

Last Modified: 07/13/2009

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