Study finds a mouse model for episodic neurological disorders

For years, physicians have noticed surprising similarities in the factors that seem to trigger attacks in such episodic neurological disorders as migraine and dyskinesia. Common triggers include psychological stress, caffeine or alcohol ingestion, fatigue, hormonal fluctuations and exercise.

A new study shows that a mouse model can be used to investigate how these substances and environmental factors trigger symptomatic attacks. The researchers also identified two drugs that can prevent attacks of such disorders in mice.

The study is the first to use mice to investigate triggers of episodic attacks, which are much more difficult to study in humans. Though the symptoms of episodic disorders vary, the fact that many of them share the same trigger factors may suggest a common disease mechanism.

“We finally have a model we can use to find out how these triggers destabilize nervous system function,” says senior author Ellen Hess, Ph.D., of the Department of Neurology at Johns Hopkins Hospital, where the study was conducted. It was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the August, 2002, issue of Pharmacology, Biochemistry and Behavior.

Dr. Hess and her colleagues studied a strain of mice with a gene mutation that causes them to have attacks of dyskinesia, or abnormal movements several times a day. The mutation affects calcium ion channels – tiny “gates” in cell membranes that control movement of electrically charged calcium ions into and out of cells. The movement disorder caused by this mutation is known as tottering syndrome in mice. The symptoms in tottering mice are similar to those of an episodic movement disorder in humans known as paroxysmal dyskinesia.

The researchers exposed the tottering mice to the most common triggers of human episodic disorders – stress, caffeine, and ethanol – and found that all three of these factors generated attacks in the mice. This shows that the tottering mice can be used to study how environmental factors cause episodic symptoms. The researchers also tested two drugs that block calcium ions from entering cells and found that these drugs could prevent tottering attacks in the mice. The first drug, nimodipine, blocked caffeine- and ethanol-induced attacks in the mice, while the second drug, MK801, blocked caffeine- and stress-triggered attacks.

“We can use the mouse model to understand how triggers work in single gene disorders, which are fairly rare, and then apply the information to more prevalent episodic disorders, like common migraine,” says lead author Brandy Fureman, Ph.D., of the NINDS. The term common migraine refers to migraines that are not preceded by other neurological symptoms (auras). These headaches affect an estimated 20 to 24 million people in the United States. Other episodic neurological disorders include periodic paralysis, hemiplegic migraine, and episodic ataxia.

“The study opens up a whole new way to look at triggers of attacks. Stress, caffeine and alcohol are factors we’ve all known about for years, but we still haven’t figured out why they can cause certain symptoms in certain people,” says Dr. Fureman. Now, researchers will be able to control the onset of attacks in studies of mice to learn how trigger factors cause a shift from normal brain function to the abnormal activity that causes symptoms.

Because common migraine and other episodic neurological disorders have the same triggers as the tottering syndrome in mice, the researchers hope that their findings will improve understanding of these disorders and lead to effective treatments for humans.

One of the drugs tested, nimodipine, is commonly used in humans to treat cardiac problems like hypertension. “We are finding a new use for an old drug,” Dr. Fureman says. “Drugs that have already gone through the FDA’s rigorous safety testing, like nimodipine, are easier to move into clinical trials once the basic research progresses to that point.”

“The next step is to start testing drugs that we think can interfere with those three triggers to stop the neurological dysfunction in humans,” says Dr. Hess. She and her colleagues are now using the tottering mice to test compounds that are currently used by humans for other disorders.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.

Fureman BE, Jinnah HA, Hess EJ. “Triggers of paroxysmal dyskinesia in the calcium channel mouse mutant tottering.” Pharmacology, Biochemistry and Behavior, Vol. 73, No. 2, August 2002.