Memis Idil, Mittal Rahul, Furar Emily, White Isaiah, Eshraghi Rebecca S, Mittal Jeenu, Eshraghi Adrien A
Hearing Research and Communication Disorders Laboratory, Department of Otolaryngology, Neurotology Division, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
J Clin Med. 2022 May 11;11(10):2725. doi: 10.3390/jcm11102725.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in rats. We observed that the BBB permeability was significantly increased in rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of rats, suggesting oxidative stress. Brain sections from rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征为三种核心症状，具体表现为社交行为受损、刻板/重复行为以及感觉/沟通缺陷。尽管ASD的确切病理生理学仍不明确，但宿主遗传学、氧化应激和血脑屏障（BBB）受损已被认为与ASD的易感性有关。在遗传学方面，诸如 等基因的突变与患ASD易感性增加有关。尽管一些研究观察到相互矛盾的结果，表明 与ASD无关联，但其他调查将该基因与自闭症联系起来。此外，由于CNTNAP2介导的信号传导在神经发育、神经传递和突触可塑性中起关键作用，通常认为其在神经系统疾病中发挥作用。在本研究中，我们研究了 大鼠的血脑屏障完整性和氧化应激。我们观察到，通过异硫氰酸荧光素 - 葡聚糖和伊文思蓝测定法确定，与同窝野生型（WT）动物相比， 大鼠的血脑屏障通透性显著增加。在 大鼠的脑匀浆中观察到高水平的硫代巴比妥酸反应性物质和较低量的还原型谷胱甘肽，表明存在氧化应激。 大鼠的脑切片显示诱导型一氧化氮合酶免疫染色强烈，而在WT动物中未检测到。脑匀浆中一氧化氮的定量分析显示，与对照组相比， 大鼠中的水平显著升高。由于在ASD个体中已观察到血脑屏障通透性增加和氧化应激，我们的结果表明 大鼠具有较高的构念效度和表面效度，可用于探索开发有效的治疗方法。
