Anti-asthma drug montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling.

Researchers studied montelukast, a common asthma medicine, and found it might increase autism risk. In lab studies, the drug disrupted important brain development pathways and caused autism-like behaviors in animals. A survey of children in China suggested those who took this asthma medicine early in life had higher autism rates. The study suggests this medication should be used more carefully in young children.

This study investigated montelukast (MTK), a common asthma medication, as a potential risk factor for autism spectrum disorders. Using laboratory models including rat neurons, brain organoids, and animal studies, researchers found that MTK disrupts retinoic acid signaling pathways critical for brain development. Prenatal or early postnatal MTK exposure induced autistic-like behaviors in rats, which were reduced when retinoic acid was supplemented. Molecular analysis showed MTK physically interacts with retinoic acid receptors.

A multi-center survey of a Chinese ASD cohort suggested MTK administration during early childhood may increase ASD risk. The findings propose MTK as a previously unrecognized environmental risk factor for autism.

Findings suggest need for cautious use of montelukast in pregnant women and young children. However, more research is needed before changing clinical practice. Healthcare providers should weigh asthma treatment benefits against potential neurodevelopmental risks when prescribing to vulnerable populations.

Study relies heavily on animal models and brain organoids. Human evidence limited to observational survey data from one population. Sample sizes not reported. Causal relationships in humans not established.

Autism spectrum disorders (ASD) affect approximately 1.0% of children worldwide with still increasing global prevalence. The fact that genetic factors contribute to less than 50% of ASD suggests some critical yet enigmatic roles of non-genetic factors in ASD etiology. Here, we reported that montelukast (MTK), a cysteinyl leukotriene receptor antagonist and one of the most commonly prescribed anti-asthma drugs, potently disrupted neuronal retinoic acid (RA) signaling and altered synaptic plasticity of the primary neurons from rat pre-frontal cortex (PFC). Prenatal or early postnatal exposure to MTK induced autistic-like behaviors in wild-type rats, which could be significantly alleviated by supplementing all-trans retinoic acid (atRA).

MTK altered neuronal RA signaling and forebrain patterning in brain organoids derived from human embryonic stem cells through antagonizing RA in RA signaling. Meanwhile, molecular docking followed by biochemical validation strongly indicated that MTK could physically interact with RA receptors (RARs), e.g. RA receptor α (RARA). Furthermore, multi-center survey with a large Chinese ASD cohort suggested that MTK administration during early childhood might indeed increase the risk of ASD in children.

Altogether, our findings have not only established MTK use as a yet unrecognized risk factor for human ASD, but highlighted the key importance of safer use of medicines to prevent ASD.