June 12, 2007 Northwestern University researchers have discovered a drug that slows -- and may even halt -- the progression of Parkinson's disease. The drug rejuvenates aging dopamine cells, whose death in the brain causes the symptoms of this devastating and widespread disease.
D. James Surmeier, the Nathan Smith Davis Professor and chair of physiology at Northwestern University's Feinberg School of Medicine, and his team of researchers have found that isradipine, a drug widely used for hypertension and stroke, restores stressed-out dopamine neurons to their vigorous younger selves. The study is described in a feature article in the international journal Nature, which will be published on-line June 10.
Dopamine is a critical chemical messenger in the brain that affects a person's ability to direct his movements. In Parkinson's disease, the neurons that release dopamine die, causing movement to become more and more difficult.
Ultimately, a person loses the ability to walk, talk or pick up a glass of water. The illness is the second most common neurodegenenerative disease in the country, affecting about 1 million people. The incidence of Parkinson's disease increases with age, soaring after age 60.
"Our hope is that this drug will protect dopamine neurons, so that if you began taking it early enough, you won't get Parkinson's disease, even if you were at risk. " said Surmeier, who heads the Morris K. Udall Center of Excellence for Parkinson's Disease Research at Northwestern. "It would be like taking a baby aspirin everyday to protect your heart."
Isradipine may also significantly benefit people who already have Parkinson's disease. In animal models of the disease, Surmeier's team found the drug protected dopamine neurons from toxins that would normally kill them by restoring the neurons to a younger state in which they are less vulnerable.
The principal therapy for Parkinson's disease patients currently is L-DOPA, which is converted in the brain to dopamine. Although L-DOPA relieves many symptoms of the disease in its early stages, the drug becomes less effective over time. As the disease progresses, higher doses of L-DOPA are required to help patients, leading to unwanted side-effects that include involuntary movements. The hope is that by slowing the death of dopamine neurons, isradipine could significantly extend the time in which L-DOPA works effectively.
"If we could double or triple the therapeutic window for L-DOPA, it would be a huge advance," Surmeier said.
The work by Surmeier's group is particularly exciting because nothing is known to prevent or slow the progression of Parkinson's disease.
"There has not been a major advance in the pharmacological management of Parkinson's disease for 30 years," Surmeier said.
Surmeier, who has researched Parkinson's disease for 20 years, had long been frustrated because it wasn't known how or why dopamine cells die in the disease. "It didn't seem like we were making much progress in spite of intense study on several fronts," he said.
Because he's a physiologist, Surmeier decided to investigate whether the electrical activity of dopamine neurons might provide a clue to their vulnerability. All neurons in the brain use electrical signals to do their job, much like digital computers.
First, Surmeier observed that dopamine neurons are non-stop workers called pacemakers. They generate regular electrical signals seven days a week, 24 hours a day, just like pacemaker cells in the heart. This was already known. But then he probed more deeply and discovered something very strange about these dopamine neurons.
Most pacemaking neurons use sodium ions (like those found in table salt) to produce electrical signals. But Surmeier found that adult dopamine neurons use calcium instead.
Sodium is a mild mannered ion that does its job without causing a whit of trouble to the cell. Calcium ions, however, are wild and rambunctious. Remember when Marlon Brando rode into town with his motorcycle gang in "The Wild One"" Those guys were like calcium ions.
"The reliance upon calcium was a red flag to us," Surmeier said. Calcium ions need to be chaperoned by the cell almost as soon as they enter to keep them from causing trouble, he noted. The cell has to sequester them or keep pumping them out. This takes a lot of energy.
"It's a little like having a room full of two year olds you have to watch like a hawk so they don't get into trouble," Surmeier said. "That's really going to stress you." With three boys under age eleven, he can relate to the stressed dopamine neuron.
Surmeier theorized that the non-stop stress on the dopamine neurons explains why they are more vulnerable to toxins and die at a more rapid rate as we age.
But these findings still didn't offer him a new therapy.
Then, serendipity struck when he was working on a different problem. He discovered that young dopamine neurons and adult ones have an entirely different way of operating.
When the neurons are young, Surmeier found they actually use sodium ions to do their work. But as the neurons age, they become more and more dependent on the troublesome calcium and stop using sodium. This calcium dependence -- and the stress it causes the neurons --is what makes them more vulnerable to death.
What would happen, Surmeier wondered, if he simply blocked the calcium's route into the adult neuron cells? Would the neurons revert to their youthful behavior and start using sodium again?
"The cells had put away their old childhood tools in the closet. The question was if we stopped them from behaving like adults would they go into the closet and get them out again"" Surmeier asked. "Sure enough, they did."
When he gave the mice isradipine, it blocked the calcium from entering the dopamine neuron. At first, the dopamine neurons became silent. But within a few hours, they had reverted to their childhood ways, once again using sodium to get their work done.
"This lowers the cells' stress level and makes them much more resistant to any other insult that's going to come along down the road. They start acting like they're youngsters again," Surmeier said.
The next step will be launching a clinical study.
"This animal study suggests that calcium channel blockers, drugs currently used to reduce blood pressure, might someday be used to slow the steady progression of Parkinson's disease," said Walter J. Koroshetz, M.D., deputy director of the NINDS.
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