Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease
Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease
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DOI：
10.1016/s0306-4522(98)00724-6
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发表时间：
1999-01-01
期刊：
影响因子：
3.3
通讯作者：
Gluckman, PD
中科院分区：
文献类型：
--
作者：
Hughes, PE;Alexi, T;Gluckman, PD
亨廷顿病的特征是纹状体神经元的选择性丧失，特别是中等大小的脊髓谷氨酸脱羧酶染色/ gaba能投射神经元，这些神经元共同含有钙结合蛋白calbindin。通过纹状体内注射n -甲基- d -天冬氨酸受体激动剂喹啉酸（100 nmol）损伤成年大鼠纹状体，7天后纹状体神经病理模式与亨廷顿脑相似。利用该人类亨廷顿病动物模型，研究了每天在纹状体内灌注神经细胞存活分子ActivinA（每天单次剂量0.73 μ g，连续7天）对喹啉酸诱导的各种纹状体神经元表型变性的影响。第7天，单侧纹状体内注射喹啉酸导致纹状体神经元对谷氨酸脱羧酶（51.0 +/- 5.8%）、钙结合蛋白（58.7 +/- 5.1%）、胆碱乙酰转移酶（68.6 +/- 6.1%）、NADPH-diaphorase（47.4 +/- 5.4%）、给予喹啉酸后7天，成年大鼠的小白蛋白（至58.8 +/- 4.1%）和calretinin（至60.6 +/- 8.6%）。相比之下，在服用喹啉酸后，每天一次接受纹状体内重组人ActivinA 7天的大鼠，纹状体神经元的表型变性明显减弱。ActivinA对纹状体胆碱能中间神经元群的保护作用最显著，几乎完全阻止了损伤引起的胆碱乙酰转移酶表达下降（为未损伤时的95.1 +/- 5.8%,P < 0.01）。ActivinA对小白蛋白（87.5 +/- 7.7%,P < 0.01）和NADPH-diaphorase （77.5 +/- 7.5%, P < 0.01）中间神经元群体也有显著的保护作用，但未能阻止calretinin神经元的表型变性（56.6 +/- 5.5%）。谷氨酸脱羧酶67和钙结合蛋白染色的神经细胞在很大程度上代表重叠的群体，它们都识别纹状体gaba能投射神经元。我们发现，在喹啉酸损伤后7天，ActivinA显著降低了calbindin染色的神经元数量的损失（至79.7 +/- 6.6%,P < 0.05），但没有谷氨酸脱羧酶（67）（至61.1 +/- 5.9%）。综上所述，这些结果表明，外源性给药ActivinA可以拯救纹状体中间神经元（以胆碱乙酰转移酶、小白蛋白、NADPH-diaphorase标记）和纹状体投射神经元（以calbindin标记）免受喹啉酸的兴奋性毒性损伤。需要更长期的研究来确定这些存活的表达calbinin的投射神经元是否恢复其表达谷氨酸脱羧酶(67)/ gaba能表型的能力。因此，这些结果表明，用ActivinA治疗可能有助于预防亨廷顿病中易感纹状体神经元群的退化。(c) 1999年ibro。Elsevier Science Ltd.出版。
Huntington disease is characterized by the selective loss of striatal neurons, particularly of medium-sized spiny glutamate decarboxylase(67) staining/GABAergic projection neurons which co-contain the calcium binding protein calbindin. Lesioning of the adult rat striatum by intrastriatal injection of the N-methyl-D-aspartate receptor agonist quinolinic acid (100 nmol) results in a pattern of striatal neuropathology seven days later that resembles that seen in the Huntington brain. Using this animal model of human Huntington's disease we investigated the effect of daily intrastriatal infusion of the nerve cell survival molecule ActivinA (single bolus dose of 0.73 mu g daily for seven days) on the quinolinic acid-induced degeneration of various striatal neuronal phenotypes. By seven days, unilateral intrastriatal infusion of quinolinic acid produced a partial but significant loss (P < 0.01) in the number of striatal neurons immunoreactive for glutamate decarboxylase (to 51.0 +/- 5.8% of unlesioned levels), calbindin (to 58.7 +/- 5.1%), choline acetyltransferase (to 68.6 +/- 6.1%), NADPH-diaphorase (to 47.4 +/- 5.4%), parvalbumin (to 58.8 +/- 4.1%) and calretinin (to 60.6 +/- 8.6%) in adult rats that were administered intrastriatal phosphate-buffered saline for seven days following quinolinic acid. In contrast, in rats that received intrastriatal recombinant human ActivinA once daily for seven days following quinolinic acid, phenotypic degeneration was significantly attenuated in several populations of striatal neurons. Treatment with ActivinA had the most potent protective effect on the striatal cholinergic interneuron population almost completely preventing the lesion induced decline in choline acetyltransferase expression (to 95.1 +/- 5.8% of unlesioned levels, P < 0.01). ActivinA also conferred a significant protective effect on parvalbumin (to 87.5 +/- 7.7%, P < 0.01) and NADPH-diaphorase (to 77.5 +/- 7.5%, P < 0.01) interneuron populations but failed to prevent the phenotypic degeneration of calretinin neurons (to 56.6 +/- 5.5%). Glutamate decarboxylase67 and calbindin-staining nerve cells represent largely overlapping populations and both identify striatal GABAergic projection neurons. We found that ActivinA significantly attenuated the loss in the numbers of neurons staining for calbindin (to 79.7 +/- 6.6%, P < 0.05) but not glutamate decarboxylase(67) (to 61.1 +/- 5.9%) at seven days following quinolinic acid lesioning.Taken together these results suggest that exogenous administration of ActivinA can rescue both striatal interneurons (labelled with choline acetyltransferase, parvalbumin, NADPH-diaphorase) and striatal projection neurons (labelled by calbindin) from excitotoxic lesioning with quinolinic acid. Longer-term studies will be required to determine whether these surviving calbindin-expressing projection neurons recover their ability to express the glutamate decarboxylase(67)/GABAergic phenotype. These results therefore suggest that treatment with ActivinA may help to prevent the degeneration of vulnerable striatal neuronal populations in Huntington's disease. (C) 1999 IBRO. Published by Elsevier Science Ltd.