Alexi T, Hughes P E, van Roon-Mom W M, Faull R L, Williams C E, Clark R G, Gluckman P D
School of Medicine, University of Auckland, Auckland, New Zealand.
Exp Neurol. 1999 Sep;159(1):84-97. doi: 10.1006/exnr.1999.7168.
Huntington's disease is an incurable genetic neurological disorder characterized by the relatively selective degeneration of the striatum. Lesioning of the striatum in rodents using the excitatory amino acid agonist, quinolinic acid (QA), effectively mimics the human neuropathology seen in Huntington's disease. Using this animal model of Huntington's disease, we investigated the ability of the insulin-like growth factor-I (IGF-I) amino-terminal tripeptide glycine-proline-glutamate (GPE) to protect striatal neurons from degeneration. Adult rats received a single unilateral intrastriatal injection of QA (100 nmol) and then daily injection of either vehicle or GPE (0.3 microgram/microliter/day) into the striatum for 7 days. QA at this dose resulted in a partial lesioning of the striatum after 7 days to approximately 50% of cells of unlesioned levels in vehicle-treated animals. The major striatal neuronal phenotype, GABAergic projection neurons, were identified by immunocytochemical labeling of either glutamate decarboxylase 67 (GAD(67)) or the calcium binding protein calbindin in alternate sections. Treatment with GPE for 7 days reversed the loss in projection neurons when assessed by counts of calbindin-stained cells; however, these rescued cells did not regain immunologically detectable levels of GAD(67). GPE also significantly reversed the phenotypic degeneration of cholinergic interneurons identified by immunolabeling for choline acetyltransferase (ChAT) and NADPH diaphorase interneurons identified histochemically. GPE treatment failed to rescue the calcium binding protein interneuron populations of parvalbumin and calretinin neurons. These findings reveal that exogenous administration of GPE selectively prevents excitotoxin induced phenotypic degeneration of striatal projection neurons and cholinergic and NADPH diaphorase interneurons in an animal model of Huntington's disease.
亨廷顿舞蹈症是一种无法治愈的遗传性神经疾病，其特征是纹状体相对选择性退化。使用兴奋性氨基酸激动剂喹啉酸（QA）对啮齿动物的纹状体进行损伤，可有效模拟亨廷顿舞蹈症患者的神经病理学特征。利用这种亨廷顿舞蹈症动物模型，我们研究了胰岛素样生长因子-I（IGF-I）氨基末端三肽甘氨酸-脯氨酸-谷氨酸（GPE）保护纹状体神经元免于退化的能力。成年大鼠单侧纹状体内单次注射QA（100 nmol），然后每天向纹状体内注射溶剂或GPE（0.3微克/微升/天），持续7天。该剂量的QA在7天后导致纹状体部分损伤，损伤程度约为溶剂处理动物未损伤水平细胞的50%。通过在交替切片中对谷氨酸脱羧酶67（GAD(67)）或钙结合蛋白钙结合蛋白进行免疫细胞化学标记，鉴定出主要的纹状体神经元表型，即GABA能投射神经元。通过对钙结合蛋白染色细胞计数评估，GPE处理7天可逆转投射神经元的损失；然而，这些挽救的细胞并未恢复到免疫可检测水平的GAD(67)。GPE还显著逆转了通过胆碱乙酰转移酶（ChAT）免疫标记鉴定的胆碱能中间神经元和通过组织化学鉴定的NADPH黄递酶中间神经元的表型退化。GPE处理未能挽救小白蛋白和钙视网膜蛋白神经元的钙结合蛋白中间神经元群体。这些发现表明，在亨廷顿舞蹈症动物模型中，外源性给予GPE可选择性地防止兴奋性毒素诱导的纹状体投射神经元以及胆碱能和NADPH黄递酶中间神经元的表型退化。
