An almost century-old drug restores normal metabolism in a mouse model of autism spectrum disorder (ASD), a new study reports (Transl. Psychiatry 4, e400; 2014). Metabolism and mitochondrial function are well-known regulators of neurotransmission and synaptic plasticity and likely play an important role in the development of several neurodevelopmental disorders such as ASD, which is almost universally characterized by metabolic disturbances.

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Exposure to serious infection during pregnancy or during early development causes metabolic changes that can increase the risk of neurodevelopmental disorders in offspring. Robert Naviaux, scientist at University of California San Diego School of Medicine and lead author of the study, said, “It's wrong to think of genes and the environment as separate and independent factors. Genes and environmental factors interact. The net result of this interaction is metabolism.” The maternal immune activation (MIA) mouse model of neurodevelopmental disorders, which replicates this phenomenon, produces offspring with symptoms that are biologically similar to those of ASD. In this model, pregnant females are exposed to a simulated viral infection by injection of the double stranded RNA poly(IC), which activates an evolutionarily conserved metabolic response to threat, called the 'cell danger response.' Cells that are threatened stiffen their membranes, dramatically reducing communication between cells. “Cells behave like countries at war,” Naviaux explained. “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.” Pathological persistence of this cell danger response has been observed in patients with ASD.

Naviaux's group focused on the role of nucleotides and other signaling mitokines, which are generated by distressed mitochondria, in eliciting the cell danger response. Using the antipurinergic drug suramin, which historically has been used to treat the parasitic disease trypanosomiasis or African sleeping sickness, the researchers blocked the extracellular signaling pathway used by mitokines in the MIA mouse model. The treatment reversed the cell danger response, and the related inflammation and behavioral and metabolic changes were corrected in the mice.

Unfortunately, suramin is unsafe for long-term, chronic use, limiting its clinical applications. Still, the study's authors believe that if an optimal treatment window can be identified, the drug could be used in the short term to remove the metabolic dysfunction underlying neurodevelopmental disorders like autism so that behavioral and developmental therapies can be more effective.