If a painting’s worth were measured by the money it fetched, van Gogh’s famous rendering of his friend and physician Dr. Gachet would be among the most valuable in all of art. “Portrait of Dr. Gachet”—which depicts a languid man holding a purple foxglove, the plant from which the drug digitalis is derived—was sold in 1990 for an astounding 82 million dollars. The great and famously tortured artist had his own reasons for valuing the portrait. He suffered from severe epilepsy and depended heavily on Gachet’s prescription of digitalis to treat his debilitating seizures.
The ranks of epilepsy medications have expanded considerably in the past hundred years, due mostly to the addition of pharmaceutically derived compounds. Still, people with epilepsy, who account for up to two percent of the population, may continue to suffer, either from seizures or from secondary effects associated with their medicines. “About two out of three people with epilepsy do not achieve the goal of therapy, which is seizure freedom without side effects,” said Steven Schachter, associate director of clinical research at the HMS Osher Institute and HMS professor of neurology and epileptologist at Beth Israel Deaconess Medical Center.
Part of the problem is that epilepsy is a brain disorder that has several underlying mechanisms. A drug that works in one patient may not work in another. Yet all epileptic seizures are characterized by uncontrolled electrical activity. One way to control them would be to block substances in the brain, such as glutamate, that cause neurons to fire. Pharmaceutical companies have been pressing to find glutamate-inhibiting compounds, with very limited success.
Schachter has hit upon a compound that does just that. And he has done so by drawing upon the same centuries-old botanical tradition that yielded the drug digitalis. Applying modern methods of drug discovery, he and colleagues have identified a compound derived from the spiky-looking Chinese club moss that when tested in rodents, had the power to prevent seizures. The seizures are considered to be representative of the highly debilitating grand mal, or tonic–clonic, episodes that many patients with epilepsy experience, and which are often refractory to treatment. In the fall, he hopes to launch a small clinical trial of the compound, huperzine A.
It will not be the substance’s first foray into the medical arena. For centuries, Chinese healers have been using extracts of huperzine A to quell inflammation and fever and, more recently, to treat schizophrenia. Clinical trials are under way in China and the United States to test huperzine A’s power against Alzheimer’s disease. Meanwhile, the compound is being widely marketed as an over-the-counter memory aid. But in all these years, it has not been used for the treatment of epilepsy.
Schachter, who has been seeking new methods for treating epilepsy for more than 20 years, was alerted to the promise of botanicals several years ago when he was invited by David Eisenberg to become associate director of clinical research at the Osher Institute. Eisenberg, the Bernard Osher associate professor of medicine at HMS, had been pursuing the use of botanicals in the treatment of cancer and introduced Schachter to plant-minded colleagues in this country and East Asia. Schachter set out to find herb-derived compounds for the treatment of epilepsy “using the same methods that were being used to identify potentially efficacious pharmaceuticals,” he said.
In Alzheimer’s disease, huperzine A is thought to work by blocking the enzyme that degrades acetylcholine, a neurotransmitter associated with memory. But huperzine also blocks glutamate, which suggested to Schachter that it might have potential as an anti-epileptic agent. Working with the National Institute of Neurological Disorders and Stroke and colleagues at the University of Utah, he set about testing huperzine’s mettle in a well-known rodent model of seizures, the 6-Hz model.
The researchers administered the compound to the animals and then exposed them to three levels of seizure-inducing electrical currents. Huperzine A potently prevented seizures, and it did so at all three levels. More remarkably, the dose required at the highest and lowest currents was not much different. “All other drugs that are effective in this model have shown that it takes larger doses to stop seizures as the voltage goes up, and often the difference is huge,” he said.
What makes the compound particularly ready for the prime time of clinical trials is that it is already in use, and apparently safely so. Extremely pure preparations of huperzine are available as supplements. Schachter, with funding from the Epilepsy Research Foundation, plans to give huperzine to about 20 patients who have not responded to available anti-epileptic drugs or who are experiencing side effects. “We’ll look to see how well they tolerate different dosages of huperzine, whether there’s any indication that it’s benefiting their seizures, and perhaps some early indication of any effects on their memory,” he said. He and colleagues will also be looking at how the compound might interact with other seizure medications taken by the patients.
Huperzine is just the first of several promising botanicals that Schachter hopes to test in humans. “Over the last couple of years, we’ve been building a pipeline of herbal extracts and extract-derived compounds and moving them as far as we can with basic research,” he said. In some cases, he will try to improve upon nature. For example, though huperzine worked impressively well in rodents, it was most effective when given an hour before the rats received the seizure-inducing current. “We’d like to have a drug that is effective 24 hours a day,” he said, which could require tinkering with huperzine’s pharmacokinetics.
“The overall goal of my work is to identify novel compounds that can then be developed as prescription drugs for people with epilepsy—especially those who have ongoing seizures despite available therapies or who are experiencing intolerable side effects,” said Schachter.
