Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), Brazil.
Immunobiology. 2013 Sep;218(9):1175-83. doi: 10.1016/j.imbio.2013.04.008. Epub 2013 Apr 19.
The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 μmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1β, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1β and TNF-α levels. Concomitantly, MMA increased levels of IL-1β, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.
甲基丙二酸血症是一种先天代谢缺陷（IEM），其特征是甲基丙二酸（MMA）在体液和组织中积累，导致神经功能障碍、线粒体衰竭和氧化应激。尽管神经学证据表明感染和/或炎症介质促进了患者的代谢危机，但神经炎症过程在这种有机酸血症的神经病理学中的参与尚未确定。在这项实验研究中，我们使用新生 Wistar 大鼠通过皮下注射甲基丙二酸（MMA，从第 5 天到第 28 天，每天两次，根据动物年龄范围从 0.72 到 1.67 μmol/g）来诱导慢性酸中毒模型。在接下来的几天（第 29 天至第 31 天），在物体探索测试和高架十字迷宫中评估动物行为。在血液中进行了细胞差异计数和中性粒细胞计数，以及白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）水平的检测，以及大脑皮层中 IL-1β、TNF-α、诱导型一氧化氮合酶（iNOS）和 3-硝基酪氨酸（3-NT）的水平。行为测试表明，慢性注射 MMA 的动物在物体以新的配置空间排列时，识别指数（R.I.）降低，但没有表现出焦虑样行为。MMA 处理动物的血液显示多形核和中性粒细胞数量减少，单核细胞和其他细胞类型增加，以及 IL-1β 和 TNF-α 水平增加。同时，MMA 增加了大鼠大脑皮层中 IL-1β、TNF-α、iNOS 和 3-NT 的水平。总的结果表明，慢性给予 MMA 增加了大脑皮层中的促炎标志物，降低了血液中的免疫系统防御能力，与年轻大鼠中发现的行为变化一致。这使得我们推测，通过尚未阐明的机制，发育关键期的神经炎症过程可能导致甲基丙二酸血症患者认知障碍的进展。
