European Journal of Pharmacology xxx (xxxx) xxx Please cite this article as: Kanishk Luhach, European Journal of Pharmacology, https://doi.org/10.1016/j.ejphar.2020.173663 Available online 27 October 2020 0014-2999/© 2020 Elsevier B.V. All rights reserved. Full length article Attenuation of neurobehavioural abnormalities by papaverine in prenatal valproic acid rat model of ASD Kanishk Luhach a , Giriraj T. Kulkarni b , Vijay P. Singh c , Bhupesh Sharma a, d, * a Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India b Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India c CSIR-Institute of Genomics & Integrative Biology, Academy of Scientifc and Innovative Research, New Delhi, India d CNS and CVS Pharmacology, Conscience Research, Delhi, India A R T I C L E INFO Keywords: Autism PDE10A Phosphodiesterase Papaverine Neuro-infammation Oxidative stress Valproic acid Synapsin-IIa Doublecortin BDNF Neurogenesis Pearson’s correlation ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase-10A (PDE10A) inhibition has shown to provide benefts in various brain conditions. We investigated the role of a PDE10A inhibitor, papaverine on core phenotypes in prenatal-valproic acid (Pre-VPA) model of ASD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neurogenesis-DCX, neuronal survival-BDNF, synaptic transmission-synapsin-IIa, neuronal transcription factor-pCREB, neuronal infammation (IL-6, IL-10 and TNF-α) and neuronal oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, hippocampus and striatum. Pre-VPA induced impairments in social behaviour, presence of repetitive behaviour, hyper-locomotion, anxiety, and diminished nociception were studied in male Albino Wistar rats. Administration of papaverine to Pre-VPA animals resulted in improvements of social behaviour, corrected repetitive behaviour, anxiety, locomotor, and nociceptive changes. Also, papaverine resulted in a signifcant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB, IL- 10 and GSH along with signifcant decrease in TNF-α, IL-6 and TBARS in different brain areas of Pre-VPA group. Finally, high association between behavioural parameters and biochemical parameters was observed upon Pearson’s correlation analysis. Papaverine, administration rectifed core behavioural phenotype of ASD, possibly by altering protein markers associated with neuronal survival, neurogenesis, neuronal transcription factor, neuronal transmission, neuronal infammation, and neuronal oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ASD phenotypes. 1. Introduction Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders. ASD is characterised by dysfunctional social interaction, communication defcits and occurrence of stereotypical or repetitive behaviour (Lai et al., 2014). Several co-morbid traits, including anxiety, seizure activity, motor abnormalities, aggressive behaviour and sleep disturbances occur with ASD (Matson and Cervantes, 2014). Pre-natal exposure towards valproic acid (VPA), results in development of core ASD like symptoms and to some extent secondary symptoms, in the male offspring by causing neural tube defects (Kumar and Sharma, 2016a; Schneider and Przewłocki, 2005). The VPA rat model is known to reduce the levels of phosphorylated – cAMP response element binding protein (pCREB), brain derived neurotropic factor (BDNF) and doublecortin (DCX) in the brains of exposed animals (Lee et al., 2016; Wu et al., 2017). Also, recent studies from our lab have indicated a signifcant alteration in levels of brain infammatory cytokines (Interleukin-6 (IL-6), IL-10 and tumour necrosis factor-alpha: TNF-α) and brain oxidative stress markers (TBARS, GSH-Glutathione) in various brain regions of the VPA model of ASD (Mirza and Sharma, 2019a, 2019bbib_Mirza_and_Sharma_2019abib_Mirza_and_Sharma_2019b). So, the prenatal VPA model is a robust and validated model for induction of ASD like condition in rats (Kumar et al., 2015; Kumar and Sharma, 2016a, 2016bbib_Kumar_and_Sharma_2016bbib_Kumar_and_Sharma_2016a). Cyclic nucleotide phosphodiesterase (PDE) are a family of enzymes responsible for degradation of cyclic nucleotides i.e. cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) * Corresponding author. Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, India. E-mail addresses: drbhupeshresearch@gmail.com, bsharma5@amity.edu (B. Sharma). Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar https://doi.org/10.1016/j.ejphar.2020.173663 Received 23 May 2020; Received in revised form 14 October 2020; Accepted 21 October 2020