过氧化物酶体增殖物激活受体-α的选择性调节剂可保护丙酸诱导的大鼠自闭症样表型。
Selective modulator of peroxisome proliferator-activated receptor-α protects propionic acid induced autism-like phenotypes in rats.
机构信息
Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, India.
Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, India; CNS Pharmacology, Conscience Research, Delhi, India.
出版信息
Life Sci. 2018 Dec 1;214:106-117. doi: 10.1016/j.lfs.2018.10.045. Epub 2018 Oct 23.
AIMS
The present study investigated the neuropharmacological role of PPAR-α modulator, fenofibrate in postnatal-propionic acid induced symptomatology related with autism spectrum disorders (ASD) in Wistar rats.
MAIN METHODS
The propionic acid (250 mg/kg, p.o.) was administered to rats from postnatal 21st day to 23rd day to induce autism-related neurobehavioral and neurobiochemical alterations in rats. Then, rats were treated with fenofibrate (100 mg/kg and 200 mg/kg, orally) from postnatal 24th day till 48th day. The social behavior (three chambers social testing apparatus), repetitive behavior (Y-maze), locomotor activity (actophotometer), anxiety (elevated plus maze) and exploratory behavior (hole board test) were assessed. Biochemically, oxidative stress (thiobarbituric acid reactive species and reduced glutathione level) and neuroinflammation (interleukin-6, tumor necrosis factor-α and interleukin-10) were evaluated in the cerebellum, brainstem and prefrontal cortex of rats.
KEY FINDINGS
Propionic acid-treated rats showed social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity. Also, these animals showed higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione level) as well as inflammation (increased in interleukin-6, tumor necrosis factor-α and decreased in interleukin-10) and inflammation in aforementioned brain-regions. Treatment with fenofibrate significantly attenuated the propionic acid induced-social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, fenofibrate also reduced the oxidative stress and neuroinflammation in propionic acid-treated rats.
SIGNIFICANCE
A selective PPAR-α agonist, fenofibrate provides neurobehavioral and neurobiochemical benefits in postnatal-propionic acid induced autism-related phenotype in rats. Thus, fenofibrate may further be studied for its possible benefits in ASD symptoms.
目的
本研究旨在探讨过氧化物酶体增殖物激活受体-α调节剂非诺贝特在新生大鼠丙酸诱导的自闭症谱系障碍（ASD）相关症状中的神经药理学作用。
方法
从新生第 21 天到第 23 天，给大鼠口服丙酸（250mg/kg），诱导大鼠出现与自闭症相关的神经行为和神经生化改变。然后，从新生第 24 天到第 48 天，给大鼠口服非诺贝特（100mg/kg 和 200mg/kg）。采用三箱社交测试装置评估社交行为，Y 迷宫评估重复性行为，活动度计评估运动活性，高架十字迷宫评估焦虑，洞板测试评估探索行为。评估小脑、脑干和前额叶皮质中的氧化应激（硫代巴比妥酸反应性物质和还原型谷胱甘肽水平）和神经炎症（白细胞介素-6、肿瘤坏死因子-α和白细胞介素-10）。
主要发现
丙酸处理的大鼠表现出社交障碍、重复性行为、过度活跃、焦虑和低探索活动。此外，这些动物的氧化应激水平升高（硫代巴比妥酸反应性物质增加，还原型谷胱甘肽水平降低），炎症水平升高（白细胞介素-6、肿瘤坏死因子-α增加，白细胞介素-10 减少），上述脑区的炎症也增加。非诺贝特治疗显著减轻了丙酸诱导的社交障碍、重复性行为、过度活跃、焦虑和低探索活动。此外，非诺贝特还降低了丙酸处理大鼠的氧化应激和神经炎症。
意义
选择性过氧化物酶体增殖物激活受体-α激动剂非诺贝特可改善新生大鼠丙酸诱导的自闭症相关表型的神经行为和神经生化变化。因此，非诺贝特可能进一步研究其在 ASD 症状中的潜在益处。
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