Tschirner Sarah K, Gutzki Frank, Schneider Erich H, Seifert Roland, Kaever Volkhard
Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany.
J Neurol Sci. 2016 Jun 15;365:169-74. doi: 10.1016/j.jns.2016.04.025. Epub 2016 Apr 16.
Lesch-Nyhan syndrome (LNS) is characterized by uric acid overproduction and severe neurobehavioral symptoms, such as recurrent self-mutilative behavior. To learn more about the pathophysiology of the disease, we quantified neurotransmitters and their metabolites in the cerebral hemisphere, cerebellum and the medulla oblongata of HPRT knockout mice, an animal model for LNS, in comparison to the corresponding wild-type. Our analyses included l-glutamate, 4-aminobutanoic acid (GABA), acetylcholine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, l-normetanephrine, epinephrine and l-metanephrine and were conducted via high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS). Among these neurotransmitter systems, we did not find any abnormalities in the HPRT knockout mouse brains. On one side, this might indicate that HPRT deficiency most severely affects dopamine signaling, while brain functioning based on other neurotransmitters is more or less spared. On the other hand, our findings may reflect a compensating mechanism for impaired purine salvage that protects the brain in HPRT-deficient mice but not in LNS patients.
莱施-奈恩综合征（LNS）的特征是尿酸生成过多以及严重的神经行为症状，如反复出现的自残行为。为了更多地了解该疾病的病理生理学，我们对次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HPRT）基因敲除小鼠（一种LNS动物模型）的大脑半球、小脑和延髓中的神经递质及其代谢产物进行了定量，并与相应的野生型小鼠进行了比较。我们的分析包括左旋谷氨酸、4-氨基丁酸（GABA）、乙酰胆碱、血清素、5-羟吲哚乙酸（5-HIAA）、去甲肾上腺素、左旋去甲变肾上腺素、肾上腺素和左旋变肾上腺素，通过高效液相色谱（HPLC）与串联质谱（MS/MS）联用进行。在这些神经递质系统中，我们在HPRT基因敲除小鼠的大脑中未发现任何异常。一方面，这可能表明HPRT缺乏最严重地影响多巴胺信号传导，而基于其他神经递质的脑功能或多或少未受影响。另一方面，我们的发现可能反映了嘌呤补救受损的一种补偿机制，该机制在HPRT缺乏的小鼠中保护大脑，但在LNS患者中则不然。
