Wessler Leticia B, de Miranda Ramos Vitor, Bittencourt Pasquali Matheus Augusto, Fonseca Moreira José Cláudio, de Oliveira Jade, Scaini Giselli, Streck Emilio L
Laboratório de Neurologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Int J Dev Neurosci. 2019 Nov;78:210-214. doi: 10.1016/j.ijdevneu.2019.07.007. Epub 2019 Jul 19.
Maple Syrup Urine Disease (MSUD) is an inborn error of the metabolism caused by defects in the branched a-ketoacid dehydrogenase complex (BCKDC), leading to the accumulation of branched chain amino acids (BCAAs) (leucine, isoleucine and valine). Patients with MSUD present a series of neurological dysfunction. Recent studies have been associated the brain damage in the MSUD with inflammation and immune system activation. MSUD patients die within a few months of life due to recurrent metabolic crises and neurologic deterioration, often precipitated by infection or other stresses. In this regard, our previous results showed that the inflammatory process, induced by lipopolysaccharide (LPS), associated with high levels of BCAAs causes blood-brain barrier (BBB) breakdown due to hyperactivation of MMPs. Thus, we hypothesize that the synergistic action between high concentrations of BCAAs (H-BCAAs) and LPS on BBB permeability and hyperactivation of MMPs could be through an increase in the production of cytokines and RAGE protein levels. We observed that high levels of BCAA in infant rats are related to increased brain inflammation induced by LPS administration. In addition, BCAA exposure led to an increase on brain RAGE expression of young rats. The brain inflammation was characterized by enhanced levels of interleukin 1 β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and Interferon- γ (IFN-γ), and decreased content of interleukin-10 (IL-10). Therefore, MSUD is associated with a more intense neuroinflammation induced by LPS infection.
枫糖尿症（MSUD）是一种先天性代谢缺陷疾病，由支链α-酮酸脱氢酶复合体（BCKDC）缺陷引起，导致支链氨基酸（BCAAs，即亮氨酸、异亮氨酸和缬氨酸）蓄积。MSUD患者存在一系列神经功能障碍。最近的研究表明，MSUD中的脑损伤与炎症和免疫系统激活有关。MSUD患者常因反复出现的代谢危机和神经功能恶化在出生后数月内死亡，这些情况往往由感染或其他应激因素诱发。在这方面，我们之前的研究结果显示，脂多糖（LPS）诱导的炎症过程，与高水平的BCAAs相关，会因基质金属蛋白酶（MMPs）过度激活导致血脑屏障（BBB）破坏。因此，我们推测高浓度支链氨基酸（H-BCAAs）与LPS对BBB通透性和MMPs过度激活的协同作用可能是通过细胞因子产生增加和晚期糖基化终末产物受体（RAGE）蛋白水平升高实现的。我们观察到，幼鼠体内高水平的BCAA与LPS给药诱导的脑炎症增加有关。此外，BCAA暴露导致幼鼠脑内RAGE表达增加。脑炎症的特征是白细胞介素1β（IL-1β）、白细胞介素6（IL-6）、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）水平升高，以及白细胞介素-10（IL-10）含量降低。因此，MSUD与LPS感染诱导的更强烈的神经炎症有关。
