A single dose of a century-old metabolism drug can alleviate autism-like symptoms in mice, but only temporarily. Chronic use comes with risks of toxic side-effects, though the researchers hope their findings offer “a new and fresh” look at autism and novel avenues of treatment.
Twenty percent of the known factors associated with autism are genetic, but most aren’t. "Genes and environmental factors interact. The net result of this interaction is metabolism," says Robert Naviaux from the University of California, San Diego. In neurodevelopmental disorders like autism, changes to metabolism -- the set of chemical processes that maintain our lives -- often manifest themselves in behavioral abnormalities, such as impaired social interaction and repetitive behavior.
In particular, Naviaux thinks some behaviors associated with autism may be linked to a heightened metabolic response to threat (called the “cell danger response”) interfering with brain function. Cells are surrounded by metabolites and structural units of DNA called nucleotides. When cells react defensively, their membranes stiffen and the processes of mitochondria (cellular powerplants, pictured above) are altered, dramatically reducing communication between cells.
"Cells behave like countries at war," Naviaux explains in a news release. "When a threat begins, they harden their borders. They don't trust their neighbors. But without constant communication with the outside, cells begin to function differently. In the case of neurons, it might be by making fewer or too many connections.”
He adds: “One way to look at this related to autism is this: When cells stop talking to each other, children stop talking.”
There already exists a drug that basically calms the cells down by lowering their danger response. Suramin was synthesized in 1916, and it’s used to treat a parasitic infection called African sleeping sickness. The compound binds to purine receptors, which are known to control a broad range of biological characteristics relevant to autism. These receptors are stimulated by nucleotides such as the energy molecule adenosine triphosphate (ATP) and mitokines, molecules generated by distressed mitochondria. Disrupting purine metabolism seems to activate and maintain the cell danger response.
When Naviaux and colleagues analyzed metabolic pathways in a mouse model -- with deficits in social behavior and novelty preference -- they found that purine metabolism was the most affected. So they tested suramin on 6-month old adult mice (the equivalent of a human adult) and found that a single dose restored their metabolites to typical levels. They saw similar results when they analyzed the drug's effects on behavior, such as interacting with other mice and choosing alternate routes in a maze (a measure of repetitiveness).
When suramin blocked the pathway used by ATP and mitokines, it ending the cell danger response and all the related inflammation. However, as the drug washed out of the rodents’ systems five weeks later, the behavioral and metabolic effects of their “antipurinergic therapy” diminished.
“Our idea is that this kind of treatment -- eliminating a basic, underlying metabolic dysfunction -- removes a hurdle that might make other non-drug behavioral and developmental therapies of autism more effective,” Naviaux says. “The discovery that a single dose of medicine can fundamentally reset metabolism for weeks means that newer and safer drugs might not need to be given chronically.”
The work was published in Translational Psychiatry this week.
Image: Thomas Deerinck, NCMIR, UC San Diego