中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (6): 1140-1149.doi: 10.4103/1673-5374.270316

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

腺苷酸环化酶激活剂可减轻丙酸诱导自闭症大鼠神经元线粒体的功能障碍

  

  • 出版日期:2020-06-15 发布日期:2020-07-05

Adenylate cyclase activator forskolin alleviates intracerebroventricular propionic acid-induced mitochondrial dysfunction of autistic rats

Sidharth Mehan1 , Saloni Rahi1 , Aarti Tiwari1 , Tarun Kapoor1 , Kajal Rajdev1 , Ramit Sharma1 , Himanshi Khera1 , Sourabh Kosey1 , Umesh Kukkar2 , Rajesh Dudi3   

  1. 1 Department of Neuropharmacology, ISF College of Pharmacy, Moga, Punjab, India
    2 Department of Pharmacology, Rajendra Institute of Technology & Sciences, Sirsa, Haryana, India
    3 Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
  • Online:2020-06-15 Published:2020-07-05
  • Contact: Sidharth Mehan, PhD,sidh.mehan@gmail.com.

摘要:


神经元线粒体功能障碍导致的炎症介质和自由基生成和抗氧化酶改变是自闭症的主要神经病理学标志。自闭症线粒体功能障碍与环腺苷酸单磷酸酯水平降低致ATP水平降低有关。实验给予大鼠侧脑室内注射丙酸引起记忆功能障碍,肌肉协调能力下降和平衡能力减弱,建立自闭症模型。生化评估显示自闭症模型大鼠神经元线粒体功能障碍相关的神经元线粒体电子传递链-复合物酶水平发生改变,促炎细胞因子和氧化应激和脂质生物标志物水平上升。以10,20和30mg/kg的剂量灌胃腺苷酸环化酶激活剂毛喉素15d剂量依赖性地逆转了上述变化。说明Forskolin可以减轻自闭症大鼠神经元线粒体功能障碍,改善神经系统症状。研究方案于2014年3月3日获得了机构动物伦理委员会(RITS/IAEC/2014/03/03)的批准。


orcid: 0000-0003-0034-835X (Sidharth Mehan)

关键词: 自闭症, 线粒体功能障碍, 丙酸, 毛喉素, ATP, 腺苷酸环化酶, 氧化应激, 神经炎症

Abstract: Neuronal mitochondrial dysfunction increases inflammatory mediators and leads to free radical genera- tion and anti-oxidant enzymatic alterations, which are major neuropathological hallmarks responsible for autism. Mitochondrial dysfunction in autism is associated with decreased ATP levels due to reduced levels of cyclic adenosine monophosphate. Rat models of autism were established by intracerebroventricular in- jection of propionic acid. These rat models had memory dysfunction, decreased muscle coordination and gait imbalance. Biochemical estimation of propionic acid-treated rats showed changes in enzyme activity in neuronal mitochondrial electron transport chain complexes and increases in pro-inflammatory cyto- kines, oxidative stress and lipid biomarkers. Oral administration of 10, 20 and 30 mg/kg adenylate cyclase activator forskolin for 15 days reversed these changes in a dose-dependent manner. These findings suggest that forskolin can alleviate neuronal mitochondrial dysfunction and improve neurological symptoms of rats with autism. This study was approved by the RITS/IAEC, SIRSA, HARYANA on March 3, 2014 (approval No. RITS/IAEC/2014/03/03).

Key words: adenylate cyclase, ATP, autism, forskolin, mitochondrial dysfunction, neuroinflammation, oxidative stress, propionic acid