Gabbi Patricia, Ribeiro Leandro Rodrigo, Jessié Martins Gutierres, Cardoso Alexandra Seide, Haupental Fernanda, Rodrigues Fernanda Silva, Machado Alencar Kolinski, Sperotto Brum Juliana, Medeiros Frescura Duarte M M, Schetinger Maria Rosa Chitolina, da Cruz Ivana Beatrice Mânica, Flávia Furian Ana, Oliveira Mauro Schneider, Dos Santos Adair Roberto Soares, Royes Luiz Fernando Freire, Fighera Michele Rechia, de Freitas Mayara Lutchemeyer
Programa de Pós-Graduação em Farmacologia, Centro, de, Departamento Fisiologia e Farmacologia, de Ciências da Saúde.
Laboratório de Bioquímica do Exercício, Centro, de, Departamento Métodos e Técnicas Desportivas, de Educação Física e Desportos, UFSM.
J Neuropathol Exp Neurol. 2017 Mar 1;76(3):160-178. doi: 10.1093/jnen/nlw121.
Methylmalonic acid (MMA) accumulates in tissues in methylmalonic acidemia, a heterogeneous group of inherited childhood diseases characterized by neurological dysfunction, oxidative stress and neuroinflammation; it is associated with degeneration of striatal neurons and cerebral cortical atrophy. It is presently unknown, however, whether transient exposure to MMA in the neonatal period is sufficient to trigger inflammatory and apoptotic processes that lead to brain structural damage. Here, newborn mice were given a single intracerebroventricular dose of MMA at 12 hours after birth. Maze testing of 21- and 40-day-old mice showed that MMA-injected animals exhibited deficit in the working memory test but not in the reference test. MMA-injected mice showed increased levels of the reactive oxygen species marker 2',7'-dichlorofluorescein diacetate, tumor necrosis factor, interleukin-1β, caspases 1, 3, and 8, and increased acetylcholinesterase activity in the cortex, hippocampus and striatum. This was associated with increased astrocyte and microglial immunoreactivity in all brain regions. These findings suggest that transient exposure to MMA may alter the redox state and cause neuroinflammatory/apoptotic processes and glial activation during critical periods of brain development. Similar processes may underlie brain dysfunction and cognitive impairment in patients with methylmalonic acidemia.
甲基丙二酸（MMA）在甲基丙二酸血症患者的组织中蓄积，甲基丙二酸血症是一组遗传性儿童疾病，其特征为神经功能障碍、氧化应激和神经炎症；它与纹状体神经元变性和大脑皮质萎缩有关。然而，目前尚不清楚新生儿期短暂接触MMA是否足以引发导致脑结构损伤的炎症和凋亡过程。在此，给新生小鼠在出生后12小时经脑室内注射单次剂量的MMA。对21日龄和40日龄小鼠进行的迷宫测试表明，注射MMA的动物在工作记忆测试中表现出缺陷，但在参考测试中未表现出缺陷。注射MMA的小鼠在皮质、海马体和纹状体中，活性氧标志物2'，7'-二氯荧光素二乙酸酯、肿瘤坏死因子、白细胞介素-1β、半胱天冬酶1、3和8的水平升高，乙酰胆碱酯酶活性增加。这与所有脑区星形胶质细胞和小胶质细胞免疫反应性增加有关。这些发现表明，在脑发育的关键时期短暂接触MMA可能会改变氧化还原状态，并导致神经炎症/凋亡过程和神经胶质细胞激活。类似的过程可能是甲基丙二酸血症患者脑功能障碍和认知障碍的基础。
