Prenatal exposure of azadiradione leads to developmental disabilities

Abstract

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, an ubiquitin ligase whose loss and gain of function is associated with two diverse neurodevelopmental disorders. Here we report that in uteroexposure of azadiradione in mice result in severe developmental disabilities. Treatment of well tolerated dose of azadiradione into the pregnant dam (at an embryonic day 12 and 14) causes substantial decrease in the body weight of the new-born pups at their early developmental periods along with significant cognitive, motor and communication deficits and increased anxiety-like behaviours. As the animals grow from adolescent to adult, their body weight and many behavioural 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 post natal day 25 along with significant increase some of its target proteins linked to synaptic function and plasticity indicating enduring effect of the drug on Ube3a expression. The prenatally azadiradione exposed mice also display increased number of 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.