PDE3 inhibition by cilostazol attenuated developmental hyperserotonemia induced behavioural and biochemical deficits in a rat model of autism spectrum disorder

Abstract

BackgroundHyperserotonemia, in the early developmental phase generates behavioural and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Phosphodiesterase-3 (PDE3) inhibition by cilostazol has been shown to provide benefits in various brain conditions. We investigated the role of a selective PDE3 inhibitor cilostazol on ASD related behavioural phenotypes. MethodAdministration of 5-Methoxytryptamine (5-MT) to rats perinatally (GD12-Parturition) and in early developmental stages (PND0-PND20), resulted into developmental hyperserotonemia (DHS). DHS associated behavioural changes (social behaviour deficits, repetitive behaviour, anxiety and hyperlocomotion) were assessed using a battery of behavioural examinations. Also, effect on biochemical markers related with neuronal function (BDNF – neuronal survival and pCREB – neuronal transcription factor), inflammation (IL-6, IL-10 and TNF-α) and oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus, and striatum). Cilostazol was administered in two doses 30 & 60 mg.kg-1 p.o. each day to male rats from PND21 to PND48. ResultAdministration of cilostazol to 5-MT rats resulted in improvement of behavioural deficits. Also, cilostazol administration significantly increased the levels of BDNF, pCREB, IL-10, GSH and significantly decreased TNF-α, IL-6 and TBARS levels in different brain areas. ConclusionDHS during prenatal and early postnatal developmental stages leads to pervasive harm to the serotonergic system, leading to prolonged effects as observed via behavioural and biochemical outcomes of the study. Serotonin regulates early brain neurogenesis, synaptogenesis, and neuronal differentiation probably via the CREB/BDNF pathway and DHS is known to reduce the activity of CREB/BDNF pathway. Cilostazol administration to pups exposed to DHS perinatally has resulted in increase of neurotrophic factors, reduced inflammation and reduced oxidative stress, probably via increased cAMP/CREB/BDNF signalling. Also, improvement in behavioural profile of animals subjected to DHS. Thus, PDE3 and its inhibitors could be considered as molecules of interest for research in developmental disorders.