Roots Of Epilepsy May Lie In Oft-ignored Brain Cells

Scientists found that astrocytes can serve as ground zero in thebrain, setting off a harmful cascade of electrical activity in thebrain by sending out a brain chemical that triggers other brain cellsto fire out of control.

While it's impossible to tell at this early stage what effectthe finding will have on treatment, the investigators at the Universityof Rochester Medical Center are hopeful the results will give doctorsand pharmaceutical firms a new target in efforts to treat and preventthe disease.

"This opens up a new vista in efforts to treat epilepsy. Itmight be possible to treat epilepsy not by depressing or slowing brainfunction, as many of the current medications do, but by targeting braincells that have been completely overlooked," says Maiken Nedergaard,M.D., Ph.D., professor in the Department of Neurosurgery and aresearcher in the Center for Aging and Developmental Biology, who ledthe research. "We are hopeful that someday, this will be verybeneficial to patients,"

When most people and many scientists think of brain cells, theythink of neurons, the nerve cells that send electrical signals and areat the heart of what is considered to be brain activity. In diseaseslike Alzheimer's, Parkinson's and Huntington's diseases, it's theneurons that become sick and die, and so they are the focus of intensestudy.

But neurons represent just a small proportion of brain cells.Astrocytes are present in vastly greater numbers � there areapproximately 10 times as many astrocytes as neurons in the humanbrain. Nedergaard is part of a growing group of scientists who arefocusing on the pivotal role that astrocytes may play in several humandiseases.

"The main function of astrocytes is to maintain a healthyenvironment for neurons," says Nedergaard, whose study was funded bythe National Institute of Neurological Disorders and Stroke. "Theelectrical signaling in the brain is so sophisticated that it's crucialthat the environment be optimal. There's not much room for error. Whenthe astrocytes start acting abnormally, it's easy to see how seriousdisease might result."

Last year she showed that astrocytes magnify the damage toneurons after spinal cord injury. And currently she's looking at theirrole in Alzheimer's disease.

Nedergaard notes that in epilepsy, scientists have long knownthat an early sign of the disease in the brain are abnormal cellscalled reactive astrocytes -- over-sized, bloated, star-shaped cellsthat no longer function properly. "People have thought that reactiveastrocytes were caused by epilepsy, not that they could be the cause."

In the study, Nedergaard and colleagues showed that astrocytesactually generate seizure activity, and the team linked astrocytes to abrain chemical long known to be a key player in the development ofepilepsy. They showed that glutamate, which hypes up neurons and canmake them fire uncontrollably, is released by astrocytes and cantrigger seizure-like activity in the brain.

Then the team tested medications currently used to treat thedisease. Epilepsy describes a condition in the brain where neuronsstart firing wildly and uncontrollably, sometimes resulting inseizures, and most medications aim to reduce such firing. The teamshowed that agents like gabapentin and valproate reduced the type ofchemical signaling that causes astrocytes to release glutamate.

According to Nedergaard, many scientists have thought thatepilepsy occurs when neurons that normally inhibit or slow down otherneurons lose their power, as if the brakes on a speeding car werefaulty. Current medications are aimed at making those molecular"brakes" more powerful and reining signals back in. But such drugs haveside effects like drowsiness. Her work opens up a new avenue tounderstand the disease.

"The potential role of astrocytes in the generation of epilepsyhas been largely ignored," says Michel Berg, M.D., medical director ofthe Strong Epilepsy Center. "Epilepsy involves a re-organization of thebrain's pathways, in a way that is not completely understood, thatresults in recurrent seizures. Currently we have drugs to treatseizures, but not to prevent the whole process. Perhaps someday therewill be ways to intervene before the circuitry is re-written, toprevent epilepsy completely."

More than 2 million Americans have epilepsy. Currentmedications stop seizures in about two-thirds of patients, but othersoften struggle for years or even a lifetime to cope with symptomsincluding seizures. Surgery to remove a small amount of troublesomebrain tissue is often successful in such cases. The disease can comeabout as a result of a brain injury or because of genetic abnormalitiesin the way the brain develops.

In addition to Nedergaard, the team from the University'sDepartment of Neurosurgery included Guo-Feng Tian and Weiguo Peng,research assistant professors; post-doctoral associates Takahiro Takanoand Nanhong Lou; technical associate Qiwu Xu; and graduate studentNancy Ann Oberheim. Other authors include neurosurgeon Hooman Azmi fromthe New Jersey Medical School; Jane Lin and Jian Kang of New YorkMedical College in Valhalla; and Ron Zielke of the University ofMaryland.