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A boost to brain's anti-seizure defense

Jonathan Rabinovitz

Julia Brill and John Huguenard view a tissue sample they used to gain insight into a popular epilepsy drug.

BY LOUIS BERGERON

A naturally occurring protein in our brains could be the basis for a more promising epilepsy treatment—without the nasty side effects caused by many of the current medications.

Researchers at the School of Medicine discovered that the drug valproic acid boosts the amount of the protein neuropeptide Y in the brain by about 50 percent. What's more, they found that the drug increased the protein in only two parts of the brain—the thalamus and hippocampus, areas associated respectively with petit mal and temporal lobe epileptic seizures. The neuropeptide Y levels in other parts of the brain were unaffected. "That was quite a surprise," said Julia Brill, a postdoctoral scholar in the neurology department who worked on the study.

VPA has long been a mainstay in treating epilepsy, though how it suppressed seizures was a mystery. It has a minimal sedative effect, but there's a host of other side effects—weight gain, hair loss, upset stomach and liver problems, as well as causing birth defects if taken by pregnant women—making it less than an ideal medication.

But discovering that VPA triggers an increase in neuropeptide Y not only helps explain how VPA works, it suggests a possible way to stimulate the brain to quell seizures: The key could be to increase the amount of this anti-epileptic compound in the brain. Neuropeptides are very small proteins that often help transmit signals between neurons, the specialized cells in the brain that generate and transmit thought.

"This finding emphasizes that our brains have the inherent capacity to stop seizures," said John Huguenard, PhD, associate professor of neurology and neurological sciences and senior author of a paper describing the work published in June in the Journal of Neuroscience, on which Brill is first author. Although there may be more than one mechanism by which our brains stop seizures, an increase in neuropeptide Y is clearly one of them, he said, and he and Brill are already exploring other ways to trigger production of the peptide and prolong its action.

The precise nature of this response to VPA, which is sold under the brand name Depakote, offers the promise of a new approach in treating seizures.

Unlike VPA, most anti-epileptic medications work by binding to various channels or receptors on neurons throughout the brain, thereby directly slowing the pace of signal transmission and reception. This approach to treating epilepsy is effective because seizures occur when neurons are overstimulated and fire too rapidly and in unison, sending pulsing barrages of signals through the brain. Slowing the pace of communication among the neurons prevents them from becoming overstimulated.

But a seizure often originates in just one part of the brain, so preventing seizures by slowing down the entire brain is like trying to stop cars from speeding on one particular thoroughfare by installing speed bumps on every street in town.

Huguenard and Brill said that if a way could be found to increase neuropeptide Y only in the part of the brain from which a particular type of seizure emanates, it might be possible to develop drugs with few, if any, side effects.

Robert Fisher, MD, a professor of neurology and neurological sciences who treats epileptic patients, said the findings point to a potentially better way of treating the disease. He was not involved in the study, though he has worked with Huguenard on other research.

"All of our seizure medications are controlled poisons, all with significant side effects," Fisher explained. "If we can find out more about the natural mechanisms that produce seizures, then we can hopefully counteract it with a rifle bullet rather than a shotgun that causes all kinds of side effects."

VPA is also used to treat bipolar disorders and migraine headaches; the new findings could lead to new treatments for those disorders, as well as seizures.

Brill made the discovery about VPA while working with rats. Increases of neuropeptide Y had been observed in rodent brains in response to seizures, and injections of the peptide had been shown to suppress seizures in the animals. Brill and Huguenard suspected VPA might work by somehow acting to increase the neuropeptide Y levels.

When humans are treated with VPA, they typically have increasing doses over a period of days before it takes effect. Brill set up a comparable regimen with rats. After giving them VPA doses in concentrations large enough to suppress seizures, she examined their brains and discovered the localized increases in the peptide. She also determined that after receiving the VPA, the seizure duration and the extent to which they spread from their site of origin were reduced. With epileptic seizures, an initially small seizure can spread to other parts of the brain, triggering more severe ones.

When used for treating seizures, VPA is primarily used to treat the absence epilepsy type, which mainly affects children. These are seizures that involve the thalamus, in which the sufferer appears to simply freeze for a few moments or up to half a minute. Although such seizures might appear minor, in fact they can happen dozens of times a day and have a severe effect on the ability of children to lead normal lives.

Exactly how VPA triggers the increased production of neuropeptide Y in the thalamus and hippocampus is still a challenging puzzle.

Brill said there are probably intermediate steps—a cascade of signals—leading to the boost in the neuropeptide. "If you can identify the pathway that valproic acid uses to increase the neuropeptide Y, then maybe you can figure out a different way to stimulate that same pathway and get neuropeptide Y production," she said, adding that if a way could be found to activate the signals closer to the final stage that triggers the peptide increase, "maybe you could get rid of some of the detrimental effects that valproic acid has."

"Our next step will be to understand the signaling pathways that lead to the targeted increase in NPY in the different brain regions," Huguenard added.

This work included efforts of other Stanford researchers, including Michelle Lee, Sheng Zhao and Russell Fernald, of the Department of Biological Sciences, and was supported by grants from the National Institutes of Health.