Pharmidex Pharmaceutical Services Ltd., London, UK.
Neurochem Int. 2010 Nov;57(5):504-11. doi: 10.1016/j.neuint.2010.06.013. Epub 2010 Jun 30.
Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months. The neocortex, cerebellum, hippocampus and striatum were assayed for their monoamine and monoamine metabolite content using HPLC with electrochemical detection. Striatal tyrosine hydroxylase (TOH) levels were analysed by Western blotting. In the striatum, female TASTPM mice had higher levels of DOPAC and male TASTPM mice had higher levels of 5-HIAA compared to wildtype mice. Administration of pro-oxidant diet increased striatal MHPG, turnover of NA and 5-HT levels in female TASTPM mice compared to TASTPM mice fed control diet. The pro-oxidant diet also decreased DOPAC levels in female TASTPM mice compared to those fed control diet. Striatal TOH did not depend on diet, gender or genotype. In the neocortex, the TASTPM genotype increased levels of 5-HIAA in male mice fed control diet compared to wildtype mice. In the cerebellum, the TASTPM genotype led to decreased levels of HVA (male mice only) and also decreased turnover of DA (female mice only) compared to wildtype mice. These data suggest a sparing of monoaminergic neurones in the cortex, striatum and hippocampus of TASTPM mice fed pro-oxidant diet and could be indicative of increased activity in corticostriatal circuits. The decreased cerebellar levels of HVA and turnover of DA in TASTPM mice hint at possible axonal degeneration within this subregion.
氧化应激与阿尔茨海默病（AD）的发病机制有关，导致神经退行性变和单胺神经递质减少。我们研究了给予促氧化剂饮食对表达突变 APP 和 PS-1（TASTPM 小鼠）的转基因和野生型小鼠大脑中单胺和代谢物水平的影响。3 月龄 TASTPM 和野生型（C57BL6/J）小鼠分别用正常或促氧化剂饮食喂养 3 个月。使用 HPLC-电化学检测法测定新皮质、小脑、海马和纹状体中单胺和单胺代谢物的含量。用 Western 印迹法分析纹状体酪氨酸羟化酶（TOH）水平。在纹状体中，雌性 TASTPM 小鼠的 DOPAC 水平高于野生型小鼠，雄性 TASTPM 小鼠的 5-HIAA 水平高于野生型小鼠。与 TASTPM 小鼠喂养对照饮食相比，促氧化剂饮食增加了雌性 TASTPM 小鼠纹状体 MHPG、去甲肾上腺素和 5-HT 水平的周转率。促氧化剂饮食还降低了雌性 TASTPM 小鼠的 DOPAC 水平。纹状体 TOH 不依赖于饮食、性别或基因型。在新皮质中，与野生型小鼠相比，TASTPM 基因型增加了雄性小鼠对照饮食中 5-HIAA 的水平。在小脑，与野生型小鼠相比，TASTPM 基因型导致 HVA 水平降低（仅雄性小鼠），并且 DA 周转率降低（仅雌性小鼠）。这些数据表明，在给予促氧化剂饮食的 TASTPM 小鼠的皮质、纹状体和海马中单胺能神经元得到了保留，这可能表明皮质纹状体回路的活动增加。小脑 HVA 和 TASTPM 小鼠 DA 周转率的降低提示该亚区可能存在轴突退化。
