February 7, 2014
Using Bumetanide For Chloride Reduction May Prevent Autism
redOrbit Staff & Wire Reports - Your Universe Online
Although the drug could not be administered prenatally in humans since there is no way to screen for autism in human fetuses, clinical trials in which the drug was administered to young children who have already developed autistic symptoms are showing progress, the researchers said.
The causes of autism spectrum disorder, or ASD, are complex and not well understood, although experts generally agree that the disorder has its origins in early life – fetal and/or postnatal.
Neurons contain high levels of chloride throughout the entire embryonic phase. As a result, GABA, the main chemical messenger of the brain, excites the neurons instead of inhibiting them in order to facilitate brain construction. Subsequently, a natural reduction in chloride levels allows GABA to exercise its inhibitory role and regulate the activity of the adolescent/adult brain.
In the current study, researchers made a breakthrough in understanding ASD by demonstrating that chloride levels are not only elevated in the neurons of mice used in an animal model of autism, but they remain at abnormal levels from birth.
These results corroborate the success obtained with the diuretic treatment (which reduces neuronal chloride levels) tested on autistic children in 2012, and suggest that administration of diuretics to pregnant mice before birth corrects the deficits in the offspring. The study also showed that the birth hormone oxytocin brings about a decrease in chloride level during birth, which controls the expression of the autistic syndrome.
In the current study, the researchers used two rodent models of ASD – one caused by a gene and one caused by the environmental factor of exposure to the drug valproate in utero.
Oxytocin didn't signal from mother to baby in either model, and as a result, chloride built to higher concentrations than it should have inside fetal neurons. However, by injecting the mothers with bumetanide, the researchers were able to reduce chloride levels to their appropriate amount and in turn restore the GABA switch mechanism from excitatory to inhibitory, as expected.
Critically, offspring exposed to this treatment, which was administered one day before delivery, didn't demonstrate traits of autism.
"This study validates the clinical trials using bumetanide to reduce chloride and restore strong GABAergic inhibition in humans with autism," said study author Yehezkel Ben-Ari, Inserm Emeritus Research Director at the Mediterranean Institute of Neurobiology (INMED), referring to the 2012 clinical trial done in more than 50 young children.
Additional clinical trials with the drug are being pursued in Europe.
'This is one of the most promising clinical strategies for ASD currently available,' Dr. Ben-Ari said.
"The observation that a single treatment of the mother before delivery prevents the expression of … features of autism in offspring illustrates the importance of conditions at delivery…and the amazing long-term priming consequences of a wrong start,” he said.
In other words, chloride levels during delivery appear to need to be low.
Together, the work of Ben-Ari and colleagues suggests that abnormal chloride levels may cause the defective GABA switch associated with autism, and that these chloride levels may be treatable beyond infancy.
"I think that an early diagnosis of ASD coupled with a drug such as bumetanide or other regulators acting to reduce aberrant brain activities that perturb neuronal activities are likely future therapies," Dr. Ben-Ari said.
Communicating with a child suspected to have autism as early as possible is important as well, he added.
"Behavioral treatments might be reinforced by these pharmaceutical treatments and might facilitate their success, restoring communication with the child at an early age."