Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal (IRyCIS), Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), ISCIII, Spain.
Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal (IRyCIS), Madrid, Spain.
Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Sep;1863(9):958-967. doi: 10.1016/j.bbalip.2018.05.009. Epub 2018 May 21.
Experimental autoimmune encephalomyelitis (EAE), the most common model for multiple sclerosis, is characterized by inflammatory cell infiltration into the central nervous system and demyelination. Previous studies have demonstrated that administration of some polyphenols may reduce the neurological alterations of EAE. In this work, we show that ellagic acid, a polyphenolic compound, is beneficial in EAE, most likely through stimulation of ceramide biosynthesis within the brain. EAE was induced in Lewis rats by injection of guinea-pig spinal cord tissue along with Freund's complete adjuvant containing Mycobacterium tuberculosis. Clinical signs first appeared at day 8 post-immunization and reached a peak within 3 days, coincident with reduction of myelin basic protein (MBP) in the cortex. Sphingolipids, the other major components of myelin, also decreased at the acute phase of EAE, both in the cerebral cortex and in the spinal cord. In rats receiving ellagic acid in the drinking water from 2 days before immunization, the onset of the disease was delayed and clinical signs were reduced. This amelioration of clinical signs was accompanied by sustained levels of both MBP and sphingolipid in the cortex, without apparent changes in infiltration of inflammatory CD3+ T-cells, microglial activation, or weight loss, which together suggest a neuroprotective effect of ellagic acid. Finally, in glioma and oligodendroglioma cells we demonstrate that urolithins, the ellagic acid metabolites that circulate in plasma, stimulate the synthesis of ceramide. Together these data suggest that ellagic acid consumption protects against demyelination in rats with induced EAE, likely by a mechanism involving sphingolipid synthesis.
实验性自身免疫性脑脊髓炎（EAE）是多发性硬化症最常见的模型，其特征是炎症细胞浸润中枢神经系统和脱髓鞘。先前的研究表明，一些多酚的给药可能会减轻 EAE 的神经改变。在这项工作中，我们表明，鞣花酸，一种多酚化合物，在 EAE 中是有益的，很可能是通过刺激大脑内神经酰胺的生物合成。通过用含有结核分枝杆菌的完全弗氏佐剂给豚鼠脊髓组织注射，在 Lewis 大鼠中诱导 EAE。临床症状在免疫后第 8 天首次出现，并在 3 天内达到高峰，与皮质中髓鞘碱性蛋白（MBP）的减少同时发生。鞘脂类，髓鞘的另一个主要成分，在 EAE 的急性阶段也减少，无论是在大脑皮层还是在脊髓中。在从免疫前 2 天开始在饮用水中接受鞣花酸的大鼠中，疾病的发作延迟，临床症状减轻。这种临床症状的改善伴随着皮质中 MBP 和鞘脂水平的持续升高，而浸润的炎症性 CD3+T 细胞、小胶质细胞激活或体重减轻没有明显变化，这共同表明鞣花酸具有神经保护作用。最后，我们在神经胶质瘤和少突胶质细胞瘤细胞中证明，鞣花酸的代谢产物尿石素在血浆中循环，可刺激神经酰胺的合成。这些数据表明，鞣花酸的消耗可防止诱导的 EAE 大鼠发生脱髓鞘，可能涉及鞘脂合成的机制。
