Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India.
Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India.
Eur J Pharmacol. 2021 Jan 5;890:173663. doi: 10.1016/j.ejphar.2020.173663. Epub 2020 Oct 27.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase-10A (PDE10A) inhibition has shown to provide benefits 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 inflammation (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 significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB, IL-10 and GSH along with significant 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 rectified core behavioural phenotype of ASD, possibly by altering protein markers associated with neuronal survival, neurogenesis, neuronal transcription factor, neuronal transmission, neuronal inflammation, and neuronal oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ASD phenotypes.
自闭症谱系障碍（ASD）是一种神经发育障碍，其病因和表型复杂。磷酸二酯酶-10A（PDE10A）抑制剂已被证明在各种脑部疾病中具有益处。我们研究了 PDE10A 抑制剂罂粟碱在产前丙戊酸（Pre-VPA）ASD 模型中的核心表型中的作用。为了确定可能涉及的机制，研究了几种神经元功能的蛋白标志物的影响，如神经发生-DCX、神经元存活-BDNF、突触传递-synapsin-IIa、神经元转录因子-pCREB、神经元炎症（IL-6、IL-10 和 TNF-α）和神经元氧化应激（TBARS 和 GSH）在前额皮质、小脑、海马体和纹状体中。在雄性白化 Wistar 大鼠中研究了 Pre-VPA 诱导的社会行为障碍、重复行为出现、过度活跃、焦虑和痛觉减退。在 Pre-VPA 动物中给予罂粟碱可改善社会行为、纠正重复行为、焦虑、运动和痛觉变化。此外，罂粟碱还导致 BDNF、synapsin-IIa、DCX、pCREB、IL-10 和 GSH 的水平显著增加，同时 TNF-α、IL-6 和 TBARS 在 Pre-VPA 组的不同大脑区域显著降低。最后，通过 Pearson 相关性分析观察到行为参数和生化参数之间存在高度相关性。罂粟碱的给药纠正了 ASD 的核心行为表型，可能是通过改变与神经元存活、神经发生、神经元转录因子、神经元传递、神经元炎症和神经元氧化应激相关的蛋白标志物。提示 PDE10A 可能是进一步了解 ASD 表型的潜在靶点。
