September 14, 2011
Treating Tumor-Associated Epilepsy
(Ivanhoe Newswire) -- Glioma, one of the most deadly and common types of brain tumor, is often associated with seizures, but the origins of these seizures and effective treatments for them have been elusive. Scientists have found that human gliomas implanted in mice release excess levels of the brain chemical glutamate, overstimulating neurons near the tumor and triggering seizures.
The researchers also found that sulfasalazine, a drug on the market for treating certain inflammatory disorders, can reduce seizures in mice with glioma."Seizures are a frequent symptom of glioma and are often poorly controlled by epilepsy medications," Jane Fountain, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS), was quoted as saying. "Understanding why the seizures occur and how to counteract them could help us substantially improve the quality of life for people with glioma."
Glutamate serves as a chemical relay within the brain. Its release from one neuron can stimulate other neurons to fire electrical impulses. However, excess glutamate can cause abnormal electrical activity in the brain — which is the basis for epileptic seizures. In particular, excess release of glutamate from non-neuronal cells called glia appears to play a role in some types of epilepsy. Because gliomas result from an overgrowth of glia, researchers had theorized that glutamate produced by the tumors might cause seizures, but no one had established a causal link.
Harald Sontheimer´s Ph.D. team tested the theory by studying mice whose brains were seeded with human glioma cells. They found that about one-third of the animals with gliomas developed abnormal brain activity and behavioral signs consistent with seizures. They also investigated whether or not the tumors affect brain activity in response to stimulation. When they delivered electrical pulses near a tumor, they saw a pattern of activity that spread outward from the tumor and was more prolonged and widespread than the responses to stimulation seen in normal brain tissue. Brain tissue containing the tumors also released higher levels of glutamate compared to normal brain tissue.
Next, the researchers sought to determine if the drug sulfasalazine could correct these abnormalities. Sulfasalazine is an anti-inflammatory. It also targets a protein complex called the system Xc(-) transporter. System Xc(-) acts like a commodities broker within glioma cells, importing the essential amino acid cystine into the cells in exchange for exporting glutamate.
Dr. Sontheimer's team found that by inhibiting the system Xc(-) transporter, sulfasalazine can reduce glutamate release from gliomas. The drug also reduced seizure activity in the glioma-bearing mice, cutting the frequency of epileptic bursts nearly fivefold in the first hour after treatment. After four hours, the effects of the drug wore off unless it was re-administered. The likely reason is that most of the drug is broken down into a form that does not affect system Xc(-), according to Dr. Sontheimer.
A clinical trial is planned at UAB to determine if sulfasalazine can reduce seizures in people with slow-growing gliomas. Meanwhile, Dr. Sontheimer's lab is working with medicinal chemists to develop a form of the drug that is more stable in the bloodstream and brain, and more active against system Xc(-).
"There is hope that in addition to reducing seizures, sulfasalazine might reduce the growth of glioma cells," Dr. Sontheimer was quoted as saying. The cystine molecules imported by system Xc(-) are used to manufacture vital proteins that help tumor cells grow stronger, he explained. In a 2005 study, he found that sulfasalazine delays glioma growth in mice.
SOURCE: Nature Medicine, published online September 9, 2011