Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling of Effect of Naringenin and Its Surface Modified Nanocarriers on Associated and Core Behaviors of Autism Spectrum Disorders (ASD)

Abstract

AbstractThe pharmacokinetic and pharmacodynamic (PK-PD) model was developed to describe the relationship between plasma/brain concentration of naringenin and its nanocarriers with behavioral and biochemical alterations in a rat model of autism spectrum disorders (ASD). Behavioral parameters like sensorimotor dysfunction, hyperlocomotion, anxiety-like behavior, social interaction, and repetitive behavior were investigated by rotarod, actophotometer, open-field, reciprocal social interaction, and repetitive self-grooming test respectively. Naringenin was administered in doses (25, 50, and 100 mg/kg) and in the form of its uncoated and glutathione as well as tween 80–coated PLGA nanocarriers (25 mg/kg) thrice daily (8 hourly). Sigmoid Emax model was applied to study the relationship between the concentration of naringenin in plasma/brain and behavioral effects (in terms of sensorimotor dysfunction, locomotor activity, anxiety-like behavior, social interaction ability, repetitive behavior) as well as biochemical changes (plasma levels of TNF-α, MMP-9, and HSP-70, and Pgp at BBB). Model parameters such as Eo, Emax, and EC50 indicate that maximum effect occurred after administration of GSH-coated naringenin nanoparticles and the minimum effect occurred with the 25 mg/kg dose of unencapsulated naringenin. The R2 value of 0.99 and small Akaike information criterion indicate the goodness of fit of the model. The PK-PD modeling done by sigmoid Emax model showed a positive correlation between plasma/brain drug concentration and neuroinflammatory markers as well as behaviors consistent with the ASD phenotype.