Fazzari Maria, Lunghi Giulia, Chiricozzi Elena, Mauri Laura, Sonnino Sandro
Department of Medical Biotechnology and Translational Medicine, University of Milano, 20129 Milano, Italy.
Biomedicines. 2022 Feb 2;10(2):363. doi: 10.3390/biomedicines10020363.
Gangliosides are glycosphingolipids which are particularly abundant in the plasma membrane of mammalian neurons. The knowledge of their presence in the human brain dates back to the end of 19th century, but their structure was determined much later, in the middle of the 1950s. From this time, neurochemical studies suggested that gangliosides, and particularly GM1 ganglioside, display neurotrophic and neuroprotective properties. The involvement of GM1 in modulating neuronal processes has been studied in detail by in vitro experiments, and the results indicated its direct role in modulating the activity of neurotrophin-dependent receptor signaling, the flux of calcium through the plasma membrane, and stabilizing the correct conformation of proteins, such as α-synuclein. Following, in vivo experiments supported the use of ganglioside drugs for the therapy of peripheral neuropathies, obtaining very positive results. However, the clinical use of gangliosides for the treatment of central neurodegeneration has not been followed due to the poor penetrability of these lipids at the central level. This, together with an ambiguous association (later denied) between ganglioside administration and Guillain-Barrè syndrome, led to the suspension of ganglioside drugs. In this critical review, we report on the evolution of research on gangliosides, on the current knowledge on the role played by gangliosides in regulating the biology of neurons, on the past and present use of ganglioside-based drugs used for therapy of peripheral neuropathies or used in human trials for central neurodegenerations, and on the therapeutic potential represented by the oligosaccharide chain of GM1 ganglioside for the treatment of neurodegenerative diseases.
神经节苷脂是糖鞘脂，在哺乳动物神经元的质膜中含量尤为丰富。人类大脑中存在神经节苷脂的认识可追溯到19世纪末，但直到20世纪50年代中期才确定其结构。从那时起，神经化学研究表明神经节苷脂，尤其是GM1神经节苷脂，具有神经营养和神经保护特性。GM1在调节神经元过程中的作用已通过体外实验进行了详细研究，结果表明其在调节神经营养因子依赖性受体信号传导活性、钙通过质膜的通量以及稳定蛋白质（如α-突触核蛋白）的正确构象方面具有直接作用。随后，体内实验支持使用神经节苷脂药物治疗周围神经病变，并取得了非常积极的结果。然而，由于这些脂质在中枢水平的穿透性较差，神经节苷脂在治疗中枢神经退行性疾病方面尚未得到临床应用。这一点，再加上神经节苷脂给药与格林-巴利综合征之间存在模糊的关联（后来被否认），导致神经节苷脂药物的停用。在这篇批判性综述中，我们报告了神经节苷脂研究的进展、关于神经节苷脂在调节神经元生物学中所起作用的当前知识、过去和现在用于治疗周围神经病变或用于中枢神经退行性疾病人体试验的基于神经节苷脂的药物的使用情况，以及GM1神经节苷脂的寡糖链在治疗神经退行性疾病方面的治疗潜力。
