Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Brazil; Laboratório de Bioquímica do Exercício, Departamento de Métodos e Técnicas Desportivas, Centro de Educação Física e Desportos, UFSM, Brazil; Departamento de Neuropsiquiatria, Centro de Ciências da Saúde, UFSM, Brazil.
Laboratório de Bioquímica do Exercício, Departamento de Métodos e Técnicas Desportivas, Centro de Educação Física e Desportos, UFSM, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Brazil; Departamento de Neuropsiquiatria, Centro de Ciências da Saúde, UFSM, Brazil.
Toxicol Lett. 2018 Oct 1;295:237-248. doi: 10.1016/j.toxlet.2018.06.1070. Epub 2018 Jul 7.
Hyperammonemia is a common finding in patients with methylmalonic acidemia. However, its contribution to methylmalonate (MMA)-induced neurotoxicity is poorly understood. The aim of this study was evaluate whether an acute metabolic damage to brain during the neonatal period may disrupt cerebral development, leading to neurodevelopmental disorders, as memory deficit. Mice received a single intracerebroventricular dose of MMA and/or NHCl, administered 12 hs after birth. The maze tests showed that MMA and NHCl injected animals (21 and 40 days old) exhibited deficit in the working memory test, but not in the reference memory test. Furthermore, MMA and NHCl increased the levels of 2',7'-dichlorofluorescein-diacetate (DCF), TNF-α, IL-1β in the cortex, hippocampus and striatum of mice. MMA and NHCl also increased glial proliferation in all structures. Since the treatment of MMA and ammonia increased cytokines levels, we suggested that it might be a consequence of the glial activation induced by the acid and ammonia, leading to delay in the developing brain and contributing to behavioral alterations. However, this hypothesis is speculative in nature and more studies are needed to clarify this possibility.
高氨血症是甲基丙二酸血症患者的常见表现。然而，其对甲基丙二酸（MMA）诱导的神经毒性的作用仍不清楚。本研究旨在评估新生儿期大脑的急性代谢损伤是否会破坏大脑发育，导致神经发育障碍，如记忆缺陷。小鼠在出生后 12 小时接受单次脑室内 MMA 和/或 NHCl 注射。迷宫测试表明，MMA 和 NHCl 注射的动物（21 天和 40 天龄）在工作记忆测试中表现出缺陷，但在参考记忆测试中没有缺陷。此外，MMA 和 NHCl 增加了皮层、海马体和纹状体中 2'，7'-二氯荧光素二乙酸酯（DCF）、TNF-α 和 IL-1β 的水平。MMA 和 NHCl 也增加了所有结构中的神经胶质细胞增殖。由于 MMA 和氨处理增加了细胞因子的水平，我们认为这可能是酸和氨诱导的神经胶质细胞激活的结果，导致发育中的大脑延迟，并导致行为改变。然而，这种假设本质上是推测性的，需要更多的研究来澄清这种可能性。
