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Stanford University School of Medicine

Tiny drug-bearing balls of gold may be just the right size to quench dementia

sunThat gold ball in the distance may not be the sun, but it might make future dementia patients' day, someday.

Stanford molecular bioengineer Alex Savtchenko, PhD, has devised a newfangled nanoparticle whose center is a small ball of gold. It may turn out to be a more effective and safer drug than memantine, which is approved for moderate and severe cases of Alzheimer's but has never shown much evidence of efficacy for the mild version of the disease. If the nanoparticle's beneficial effects hold up in clinical trials, it could perhaps be put to work earlier in the course of the disease.

In principle, the novel concept -- described in a study published in Nano Letters -- could also see duty in other chronic neurodegenerative diseases such as Huntington's and Parkinson's diseases as well as ischemic stroke and traumatic brain injury. That's because each of these has been linked, at least in part, to a common source of damage to nerve cells that's called excitotoxity, precisely what memantine is meant to counteract.

When it comes to communication it takes two to tango, and the brain is no exception. Specialized chemicals known as neurotransmitters, having been secreted from from the tip of one nerve cell, bind to receptors on another nerve cell and either excite or inhibit activity in the receiver cell.

There are many different types of nerve cells, and many correspondingly different types of neurotransmitters. The main excitatory neurotransmitter -- glutamate -- is associated with about half of all nerve cells, and well over nine out of every 10 connections between them, in the human brain.

For the most part, nerve cells communicate across so-called synapses: specific places where two nerve cells all but make contact with one another. One cell contains equipment dedicated to secreting a particular type of neurotransmitter, while the other cell is loaded with receptors that can latch onto molecules of that specific neurotransmitter after those molecules have diffused across the minute gap separating the sending from the receiving nerve cell.

But although largely concentrated in synapses, those receptors also show up on other parts of nerve cells. And, it turns out, those so-called extrasynaptic receptors can exert physiological effects that differ from those of identical receptors located at synapses of the same nerve cell.

For example, it seems that excitotoxicity, brought about by glutamate-induced hyperactivity in the brain's many glutamate-activated circuits, is more the result of extrasynaptic-receptor stimulation than of synaptic-receptor stimulation.

So Savtchenko and his colleagues, using tiny bridges made of a medically safe variant of polyethylene glycol (the main ingredient in antifreeze), coupled multiple molecules of memantine to single minuscule balls of gold (at 13 nanometers in diameter, a bit thicker than the length an average scientist's beard grows in one second).

The resulting memantine-saturated nanoparticles were too big to fit into a synapse -- so they couldn't interact with synaptic glutamate receptors -- but were able to reach the extrasynaptic receptors that appear to be the key drivers of dementia and other neuropsychiatric disorders. In preclinical tests, the nanoparticles produced many of memantine's good effects (and in an enhanced way) but none of the bad ones.

Great balls of fire.

Previously: Minuscule DNA ring tricks tumors into revealing their presence, Dynamic duo: Nanoparticle/prodrug combination finds and fights tumors, files reports, Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they're making new knees and Nanoparticles home in on human tumors growing in mice's brains, increase accuracy of surgical removal
Photo by John Brennan

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