Prenatal Exposure to Azadiradione Leads to Developmental Disabilities

Azadiradione is a brain-permeable phytochemical present in the seed of an Indian medicinal plant, Azadirachta Indica, well known as neem. Recently, this small bioactive molecule has been revealed to induce the expression of Ube3a, a ubiquitin ligase whose loss and gain of function are associated with two diverse neurodevelopmental disorders. Here, we report that in utero exposure to azadiradione in mice results in severe developmental disabilities. Treatment of a well-tolerated dose of azadiradione into the pregnant dam (at embryonic days 12 and 14) causes a substantial decrease in the body weight of the newborn pups during their early developmental periods along with significant cognitive, motor, and communication deficits and increased anxiety-like behaviors. As the animals grow from adolescence to adulthood, their body weight and many behavioral deficits are gradually restored to normalcy, although the cognitive deficit persists significantly. Biochemical analysis reveals that the azadiradione prenatally exposed mice brain exhibits about 2-3 fold increase in the level of Ube3a at postnatal day 25 along with a significant increase in some of its target proteins linked to synaptic function and plasticity, indicating the enduring effect of the drug on Ube3a expression. The prenatally azadiradione-exposed mice also display increased dendritic spines in the hippocampal and cortical pyramidal neurons. These results suggest that Ube3a might be one of the key players in azadiradione-induced developmental disabilities.