September 12, 2011 — Administration of sulfasalazine may help reduce the frequency of epileptic seizures in patients with glioma, results of an animal study suggest.
Using mice whose brains were seeded with human glioma cells, investigators connected seizure activity to excess release of the neurotransmitter glutamate from tumor cells, an effect that was curtailed by administering sulfasalazine at a dose equivalent to that typically taken by patients with Crohn's disease.
The study results were published online September 11 in Nature Medicine.
"People have assumed that tumors cause seizures by irritating the brain, but that really isn't a scientific explanation," said Harald Sontheimer, PhD, the chief investigator and a professor of neurobiology and director of the Center for Glial Biology in Medicine at the University of Alabama at Birmingham, in the news release. "We have now shown that the seizures are caused by glutamate release from the tumor."
A clinical trial is being planned to evaluate the ability of sulfasalazine to reduce seizures in people with slow-growing gliomas. Dr. Sontheimer's laboratory is also working with medicinal chemists to formulate a version of the drug that is more stable in the blood and brain, and more effective in blocking system Xc −.
"Seizures are a frequent symptom of glioma and are often poorly controlled by epilepsy medications," Jane Fountain, PhD, a program director at the National Institutes of Health's National Institute of Neurological Disorders and Stroke, commented in an agency news release. "Understanding why the seizures occur and how to counteract them could help us substantially improve the quality of life for people with glioma."
Gliomas arise from the glial supportive tissue of the brain and represent the deadliest and most common form of primary brain tumors. About 80% of patients with glioma experience at least 1 seizure, often as an initial symptom; 33% will go on to develop recurring seizures, known as tumor-associated epilepsy.
In a study supported by the National Institutes of Health, the researchers found that 37.2% of glioma-implanted mice developed spontaneous, recurring, and unprovoked abnormal electroencephalogram activity that increased progressively over time. Behavioral signs consistent with rodent seizures were also present, including freezing behavior with facial automatisms and head tremor. No epileptic activity was observed in the control mice.
Cortical slices from the glioma-bearing mice showed a time-dependent increase in glutamate release compared with in controls, combined with a more prolonged and widespread response to electrical stimulation.
Researchers next hypothesized that the epileptic activity could be reduced by administering sulfasalazine at an equivalent dose to that typically taken by patients with Crohn's disease.
Sulfasalazine is an anti-inflammatory drug that also targets a protein complex known as the system cystine/glutamate (Xc −) transporter, which couples cystine uptake with excessive glutamate release in gliomas.
Results showed that blocking system Xc − with sulfasalazine yielded a significant decrease in glutamate release from gliomas, and a 5-fold decrease in epileptic bursts during the first hour after treatment (0.356 ± 0.091 vs 1.733 ± 0.22 for controls; P < .001). After 4 hours, the effect wore off, which is consistent with sulfasalazine's relatively short half-life (~80 minutes). Similar efficacy was observed on drug readministration.
No Benefit Seen Previously
Sulfasalazine may also slow tumor growth by blocking the import of essential cystine molecules, as demonstrated by Dr. Sontheimer in a 2005 study.
According to the news release, it is unclear whether these promising results with sulfasalazine in animal studies will translate into improved outcomes in patients with glioma. No benefit was observed in a small trial of 10 patients with advanced-stage gliomas treated with varying doses of sulfasalazine; moreover, safety concerns arose about whether treatment worsened brain swelling near the tumor, causing the study to be terminated early.
"It is worth examining whether or not the drug can help patients with newly diagnosed, slow-growing gliomas, as opposed to patients with advanced disease," Dr. Sontheimer said.
The study was supported by the National Institutes of Health's National Institute of Neurological Disorders and Stroke and a center core grant from the National Institutes of Health Blueprint for Neuroscience Research. Lead author Dr. Sontheimer and another author received support from the National Institute of Neurological Disorders and Stroke Training Program in Brain Tumor Biology at the University of Alabama at Birmingham. One author was supported by an American Brain Tumor Association Basic Research Fellowship.
Nat Med. Published online September 11, 2011. Abstract