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A Potent Diuretic as Autism Treatment?

Animal study may show how experimental treatment “flips a switch” in brain; Autism Speaks Chief Science Officer urges caution
February 06, 2014

French researchers have used a rodent study to show how their experimental treatment for autism – the potent diuretic bumetanide – may flip a biochemical switch in the brain. Their report appears today in Science.

“This study offers the field of medicines discovery in autism an intriguing new mechanism of action to consider,” comments Autism Speaks Chief Science Officer Rob Ring.

The research team from the French Institute of Health and Medical Research (INSERM) has explored using bumetanide as an experimental treatment for autism in small clinical trials involving children. The two lead investigators, psychiatrist Eric Lemonnier and physiologist Yehezkel Ben-Ari, have founded a company that is developing bumetanide as an autism treatment. The medication’s FDA-approved use is for treating edema related to congestive heart failure or kidney disease.

In their new animal study, the researchers administered bumetanide to two types of rodents before the pregnant animals gave birth. (See figure at right.) One type consisted of mice with the gene defect that causes Fragile X syndrome in humans. The other consisted of rats exposed prenatally to the drug valproate. Both have altered behaviors similar to some symptoms of autism.

Administration of bumetanide to the pregnant rodents immediately before birth appeared to prevent the pups from developing autism-like behaviors. Their behavior was not significantly different from that of a comparison group of mice and rats.

“It’s perfectly fine to be excited about findings like this, but it’s incredibly important to understand that this shouldn’t inspire families to consider bumetanide as a treatment for their loved ones,” Dr. Ring emphasizes. “There are still many things we don’t understand about how it works, as well as some obvious safety considerations that need to be rigorously explored before its use in treating autism should be seriously discussed.”

Nor were the researchers suggesting that pregnant women take the drug. Rather, they performed the experiment to test their theory on how the drug affects brain biochemistry. According to their theory, bumetanide may indirectly restore a vital biochemical “switch” whose failure might lead to autism.

The GABA switch
Their theory is based on previous research suggesting that prolonged excitation of neurons (brain nerve cells) may be partly to blame for autism. This has led to broad interest in the neurotransmitter GABA, which can inhibit brain signaling.

But GABA’s actions are anything but simple. During prenatal brain development, GABA appears to excite brain cells. Then at birth, GABA’s action appears to switch to an inhibiting role that continues through life.

Some research suggests that the “GABA switch” is flipped by a surge of the hormone oxytocin from the infant’s mother. If the switch fails to happen, the study’s authors suggest, the neurons remain over-excited, producing autism.

In their study, the investigators found evidence that bumetanide restores the normal GABA switch at birth by reducing high levels of chloride inside neurons. Chloride is a key regulator of GABA’s actions.

Previous clinical trials
In 2012, Drs. Lemonnier and Ben-Ari reported on the promising results of a small clinical trial with 60 children with Asperger syndrome, a type of autism. A three-month course of daily bumetanide temporarily reduced the severity of autism symptoms in three-quarters of the children. The treatment also produced low potassium levels, the drug’s common side effect. This was treated with potassium supplements. The researchers are now conducting additional clinical trials in Europe.

“Animal studies such as the one reported today are extremely important for guiding our search for new autism treatments,” says Dr. Ring. “But I would like to see many loose ends be tied up before this particular compound makes the leap into trials with people.”

For instance, Dr. Ring notes that the animal models used in the experiment represent, at best, a tiny slice of the many underlying causes of autism. He calls for further study in a broader range of animal models to guide the design of future clinical trials.

“Understandably, there’s tremendous pressure to move autism treatments forward because we have far too few available,” Dr. Ring concludes. “For these reasons, we must continue to use all our resources to find and develop safe and effective options.”