Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Brain Res. 2012 Nov 5;1483:96-104. doi: 10.1016/j.brainres.2012.09.021. Epub 2012 Sep 17.
Lack of dystrophin in Duchenne muscle dystrophy (DMD) and in the mutant mdx mouse results in progressive muscle degeneration, structural changes at the neuromuscular junction, and destabilization of the nicotinic acetylcholine receptors (nAChRs). One-third of DMD patients also present non-progressive cognitive impairments. Considering the role of the cholinergic system in cognitive functions, the number of nAChR binding sites and the mRNA levels of α4, β2, and α7 subunits were determined in brain regions normally enriched in dystrophin (cortex, hippocampus and cerebellum) of mdx mice using specific ligands and reverse-transcription polymerase chain reaction assays, respectively. Membrane preparations of these brain regions were obtained from male control and mdx mice at 4 and 12 months of age. The number of [³H]-cytisine (α4β2) and [¹²⁵I]-α-bungarotoxin ([¹²⁵I]-αBGT, α7) binding sites in the cortex and cerebellum was not altered with age or among age-matched control and mdx mice. A significant reduction in [³H]-cytisine (48%) and [¹²⁵I]-αBGT (37%) binding sites was detected in the hippocampus of mdx mice at 12 months of age. When compared with the age-matched control groups, the mdx mice did not have significantly altered [³H]-cytisine binding in the hippocampus, but [¹²⁵I]-αBGT binding in the same brain region was 52% higher at 4 months and 20% lower at 12 months. mRNA transcripts for the nAChR α4, β2, and α7 subunits were not significantly altered in the same brain regions of all animal groups. These results suggest a potential alteration of the nicotinic cholinergic function in the hippocampus of dystrophin-deficient mice, which might contribute to the impairments in cognitive functions, such as learning and memory, that have been reported in the dystrophic murine model and DMD patients.
在杜氏肌营养不良症（DMD）和突变型 mdx 小鼠中，缺乏肌营养不良蛋白会导致进行性肌肉退化、神经肌肉接头的结构变化以及烟碱型乙酰胆碱受体（nAChR）的不稳定。三分之一的 DMD 患者还表现出进行性认知障碍。鉴于胆碱能系统在认知功能中的作用，使用特定的配体和逆转录聚合酶链反应测定法，分别确定了 mdx 小鼠富含肌营养不良蛋白的脑区（皮质、海马体和小脑）中的 nAChR 结合位点数量和α4、β2 和α7 亚基的 mRNA 水平。从 4 个月和 12 个月龄的雄性对照和 mdx 小鼠中获得这些脑区的膜制剂。在皮质和小脑体中，[³H]-细胞松弛素（α4β2）和[¹²⁵I]-α-银环蛇毒素（[¹²⁵I]-αBGT，α7）结合位点的数量不因年龄或年龄匹配的对照和 mdx 小鼠而改变。在 12 个月龄的 mdx 小鼠海马体中，[³H]-细胞松弛素（48%）和[¹²⁵I]-αBGT（37%）结合位点的数量显著减少。与年龄匹配的对照组相比，mdx 小鼠在海马体中未发生明显改变的[³H]-细胞松弛素结合，但在同一脑区，[¹²⁵I]-αBGT 结合在 4 个月时增加了 52%，在 12 个月时减少了 20%。在所有动物组的相同脑区中，nAChR α4、β2 和α7 亚基的 mRNA 转录本均未发生显著改变。这些结果表明，在缺乏肌营养不良蛋白的 mdx 小鼠的海马体中，烟碱型胆碱能功能可能发生潜在改变，这可能导致在 DMD 患者和 DMD 小鼠模型中报告的学习和记忆等认知功能障碍。
