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Roots of epilepsy may lie in oft-ignored brain cells
August 15, 2005Star-shaped brain cells that are often overlooked by doctors and scientists as mere support cells appear to play a key role in the development of epilepsy, researchers say in a study published on-line August 14 in Nature Medicine. It's one of the first times scientists have produced firm evidence implicating the cells, known as astrocytes, in a common human disease.
Scientists found that astrocytes can serve as ground zero in the brain, setting off a harmful cascade of electrical activity in the brain by sending out a brain chemical that triggers other brain cells to fire out of control.
While it's impossible to tell at this early stage what effect the finding will have on treatment, the investigators at the University of Rochester Medical Center are hopeful the results will give doctors and pharmaceutical firms a new target in efforts to treat and prevent the disease.
"This opens up a new vista in efforts to treat epilepsy. It might be possible to treat epilepsy not by depressing or slowing brain function, as many of the current medications do, but by targeting brain cells that have been completely overlooked," says Maiken Nedergaard, M.D., Ph.D., professor in the Department of Neurosurgery and a researcher in the Center for Aging and Developmental Biology, who led the research. "We are hopeful that someday, this will be very beneficial to patients,"
When most people and many scientists think of brain cells, they think of neurons, the nerve cells that send electrical signals and are at the heart of what is considered to be brain activity. In diseases like Alzheimer's, Parkinson's and Huntington's diseases, it's the neurons that become sick and die, and so they are the focus of intense study.
But neurons represent just a small proportion of brain cells. Astrocytes are present in vastly greater numbers - there are approximately 10 times as many astrocytes as neurons in the human brain. Nedergaard is part of a growing group of scientists who are focusing on the pivotal role that astrocytes may play in several human diseases.
"The main function of astrocytes is to maintain a healthy environment for neurons," says Nedergaard, whose study was funded by the National Institute of Neurological Disorders and Stroke. "The electrical signaling in the brain is so sophisticated that it's crucial that the environment be optimal. There's not much room for error. When the astrocytes start acting abnormally, it's easy to see how serious disease might result."
Last year she showed that astrocytes magnify the damage to neurons after spinal cord injury. And currently she's looking at their role in Alzheimer's disease.
Nedergaard notes that in epilepsy, scientists have long known that an early sign of the disease in the brain are abnormal cells called reactive astrocytes - over-sized, bloated, star-shaped cells that no longer function properly. "People have thought that reactive astrocytes were caused by epilepsy, not that they could be the cause."
In the study, Nedergaard and colleagues showed that astrocytes actually generate seizure activity, and the team linked astrocytes to a brain chemical long known to be a key player in the development of epilepsy. They showed that glutamate, which hypes up neurons and can make them fire uncontrollably, is released by astrocytes and can trigger seizure-like activity in the brain.
Then the team tested medications currently used to treat the disease. Epilepsy describes a condition in the brain where neurons start firing wildly and uncontrollably, sometimes resulting in seizures, and most medications aim to reduce such firing. The team showed that agents like gabapentin and valproate reduced the type of chemical signaling that causes astrocytes to release glutamate.
According to Nedergaard, many scientists have thought that epilepsy occurs when neurons that normally inhibit or slow down other neurons lose their power, as if the brakes on a speeding car were faulty. Current medications are aimed at making those molecular "brakes" more powerful and reining signals back in. But such drugs have side effects like drowsiness. Her work opens up a new avenue to understand the disease.
"The potential role of astrocytes in the generation of epilepsy has been largely ignored," says Michel Berg, M.D., medical director of the Strong Epilepsy Center. "Epilepsy involves a re-organization of the brain's pathways, in a way that is not completely understood, that results in recurrent seizures. Currently we have drugs to treat seizures, but not to prevent the whole process. Perhaps someday there will be ways to intervene before the circuitry is re-written, to prevent epilepsy completely."
More than 2 million Americans have epilepsy. Current medications stop seizures in about two-thirds of patients, but others often struggle for years or even a lifetime to cope with symptoms including seizures. Surgery to remove a small amount of troublesome brain tissue is often successful in such cases. The disease can come about as a result of a brain injury or because of genetic abnormalities in the way the brain develops.
In addition to Nedergaard, the team from the University's Department of Neurosurgery included Guo-Feng Tian and Weiguo Peng, research assistant professors; post-doctoral associates Takahiro Takano and Nanhong Lou; technical associate Qiwu Xu; and graduate student Nancy Ann Oberheim. Other authors include neurosurgeon Hooman Azmi from the New Jersey Medical School; Jane Lin and Jian Kang of New York Medical College in Valhalla; and Ron Zielke of the University of Maryland.
University of Rochester Medical Center
"This opens up a new vista in efforts to treat epilepsy. It might be possible to treat epilepsy not by depressing or slowing brain function, as many of the current medications do, but by targeting brain cells that have been completely overlooked," says Maiken Nedergaard, M.D., Ph.D., professor in the Department of Neurosurgery and a researcher in the Center for Aging and Developmental Biology, who led the research. "We are hopeful that someday, this will be very beneficial to patients,"
When most people and many scientists think of brain cells, they think of neurons, the nerve cells that send electrical signals and are at the heart of what is considered to be brain activity. In diseases like Alzheimer's, Parkinson's and Huntington's diseases, it's the neurons that become sick and die, and so they are the focus of intense study.
But neurons represent just a small proportion of brain cells. Astrocytes are present in vastly greater numbers - there are approximately 10 times as many astrocytes as neurons in the human brain. Nedergaard is part of a growing group of scientists who are focusing on the pivotal role that astrocytes may play in several human diseases.
"The main function of astrocytes is to maintain a healthy environment for neurons," says Nedergaard, whose study was funded by the National Institute of Neurological Disorders and Stroke. "The electrical signaling in the brain is so sophisticated that it's crucial that the environment be optimal. There's not much room for error. When the astrocytes start acting abnormally, it's easy to see how serious disease might result."
Last year she showed that astrocytes magnify the damage to neurons after spinal cord injury. And currently she's looking at their role in Alzheimer's disease.
Nedergaard notes that in epilepsy, scientists have long known that an early sign of the disease in the brain are abnormal cells called reactive astrocytes - over-sized, bloated, star-shaped cells that no longer function properly. "People have thought that reactive astrocytes were caused by epilepsy, not that they could be the cause."
In the study, Nedergaard and colleagues showed that astrocytes actually generate seizure activity, and the team linked astrocytes to a brain chemical long known to be a key player in the development of epilepsy. They showed that glutamate, which hypes up neurons and can make them fire uncontrollably, is released by astrocytes and can trigger seizure-like activity in the brain.
Then the team tested medications currently used to treat the disease. Epilepsy describes a condition in the brain where neurons start firing wildly and uncontrollably, sometimes resulting in seizures, and most medications aim to reduce such firing. The team showed that agents like gabapentin and valproate reduced the type of chemical signaling that causes astrocytes to release glutamate.
According to Nedergaard, many scientists have thought that epilepsy occurs when neurons that normally inhibit or slow down other neurons lose their power, as if the brakes on a speeding car were faulty. Current medications are aimed at making those molecular "brakes" more powerful and reining signals back in. But such drugs have side effects like drowsiness. Her work opens up a new avenue to understand the disease.
"The potential role of astrocytes in the generation of epilepsy has been largely ignored," says Michel Berg, M.D., medical director of the Strong Epilepsy Center. "Epilepsy involves a re-organization of the brain's pathways, in a way that is not completely understood, that results in recurrent seizures. Currently we have drugs to treat seizures, but not to prevent the whole process. Perhaps someday there will be ways to intervene before the circuitry is re-written, to prevent epilepsy completely."
More than 2 million Americans have epilepsy. Current medications stop seizures in about two-thirds of patients, but others often struggle for years or even a lifetime to cope with symptoms including seizures. Surgery to remove a small amount of troublesome brain tissue is often successful in such cases. The disease can come about as a result of a brain injury or because of genetic abnormalities in the way the brain develops.
In addition to Nedergaard, the team from the University's Department of Neurosurgery included Guo-Feng Tian and Weiguo Peng, research assistant professors; post-doctoral associates Takahiro Takano and Nanhong Lou; technical associate Qiwu Xu; and graduate student Nancy Ann Oberheim. Other authors include neurosurgeon Hooman Azmi from the New Jersey Medical School; Jane Lin and Jian Kang of New York Medical College in Valhalla; and Ron Zielke of the University of Maryland.
University of Rochester Medical Center
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