Mehrotra Arpit, Sood Abhilasha, Sandhir Rajat
Department of Biochemistry, Panjab University, Chandigarh, 160014, India.
Mol Cell Biochem. 2015 Dec;410(1-2):281-92. doi: 10.1007/s11010-015-2561-5. Epub 2015 Sep 15.
3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces neuropathological changes similar to those observed in Huntington's disease (HD). The objective of the present study was to investigate neuroprotective effect of mitochondrial modulators; alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) on 3-NP-induced alterations in mitochondrial lipid composition, mitochondrial structure and memory functions. Experimental model of HD was developed by administering 3-NP at sub-chronic doses, twice daily for 17 days. The levels of conjugated dienes, cholesterol and glycolipids were significantly increased, whereas the levels of phospholipids (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine) including cardiolipin were significantly decreased in the mitochondria isolated from the striatum of 3-NP-treated animals. In addition, the difference in molecular composition of each phospholipid class was also evaluated using mass spectrometry. Mitochondria lipid from 3-NP-treated animals showed increased cholesterol to phospholipid ratio, suggesting decreased mitochondrial membrane fluidity. 3-NP administration also resulted in ultra-structural changes in mitochondria, accompanied by swelling as assessed by transmission electron microscopy. The 3-NP administered animals had impaired spatial memory evaluated using elevated plus maze test. However, combined supplementation with ALA + ALCAR for 21 days normalized mitochondrial lipid composition, improved mitochondrial structure and ameliorated memory impairments in 3-NP-treated animals, suggesting an imperative role of these two modulators in combination in the management of HD.
3-硝基丙酸（3-NP）是琥珀酸脱氢酶的不可逆抑制剂，可诱发与亨廷顿舞蹈病（HD）中观察到的类似的神经病理变化。本研究的目的是探讨线粒体调节剂α-硫辛酸（ALA）和乙酰-L-肉碱（ALCAR）对3-NP诱导的线粒体脂质组成、线粒体结构和记忆功能改变的神经保护作用。通过以亚慢性剂量每日两次给予3-NP，持续17天来建立HD实验模型。在从3-NP处理动物的纹状体分离出的线粒体中，共轭二烯、胆固醇和糖脂水平显著升高，而包括心磷脂在内的磷脂（磷脂酰乙醇胺、磷脂酰胆碱、磷脂酰丝氨酸）水平显著降低。此外，还使用质谱法评估了各磷脂类分子组成的差异。来自3-NP处理动物的线粒体脂质显示胆固醇与磷脂的比率增加，表明线粒体膜流动性降低。给予3-NP还导致线粒体超微结构变化，并伴有通过透射电子显微镜评估的肿胀。使用高架十字迷宫试验评估，给予3-NP的动物存在空间记忆受损。然而，联合补充ALA + ALCAR 21天可使3-NP处理动物的线粒体脂质组成正常化，改善线粒体结构并减轻记忆损伤，表明这两种调节剂联合使用在HD管理中具有重要作用。
