Beal M F, Kowall N W, Swartz K J, Ferrante R J, Martin J B
Neurology Service, Massachusetts General Hospital, Boston.
Synapse. 1989;3(1):38-47. doi: 10.1002/syn.890030106.
We previously found that quinolinic acid striatal excitotoxin lesions result in a relative sparing of somatostatin and neuropeptide Y neurons. In the present study we examined dose-response effects of excitotoxins acting at the three subtypes of glutamate receptors: N-methyl-D-aspartate (AA1), quisqualate (AA2), and kainic acid (AA3). Concentrations of both somatostatin-like immunoreactivity (SLI) and neuropeptide a Y-like immunoreactivity (NPYLI) were compared with those of substance P-like immunoreactivity (SPLI) and GABA. Kainic acid (AA3), quisqualic acid (AA2), and AMPA (AA2) resulted in dose-dependent reductions in all four neurochemical markers examined, while N-methyl-D,L-aspartate (AA1) and quinolinic acid (AA1) resulted in relative sparing of SLI and NPYLI. At doses of each excitotoxin which resulted in comparable 50% reductions in both GABA and SPLI only N-methyl-D,L-aspartate and quinolinic acid had no significant effect on concentrations of SLI and NPYLI. The relative sparing of somatostatin-neuropeptide Y neurons was confirmed histologically by using histochemical staining for NADPH-diaphorase neurons combined with either Nissl stains, or immunohistochemical staining for enkephalin. Lesions with N-methyl-D-aspartate agonists resulted in preferential sparing of NADPH-diaphorase neurons while these neurons were more vulnerable than other neurons to kainic acid or AMPA. Choline acetyltransferase neurons were relatively spared, as compared with other neurons, by agents acting at all three glutamate receptor subtypes. N-methyl-D,L-aspartate lesions were blocked with MK-801, while there was no effect on quisqualic acid or kainic acid lesions. The relative sparing of somatostatin-neuropeptide Y neurons following striatal excitotoxin lesions with N-methyl-D-aspartate (AA1) agonists probably reflects a paucity of AA1 receptors on these neurons. Since these neurons are also spared in Huntington's disease, excitotoxins acting at the N-methyl-D-aspartate (AA1) site provide an improved neurochemical model of this illness.
我们先前发现，喹啉酸纹状体兴奋毒素损伤会相对保留生长抑素和神经肽Y神经元。在本研究中，我们检测了作用于三种谷氨酸受体亚型的兴奋毒素的剂量反应效应：N-甲基-D-天冬氨酸（AA1）、quisqualate（AA2）和海人酸（AA3）。将生长抑素样免疫反应性（SLI）和神经肽Y样免疫反应性（NPYLI）的浓度与P物质样免疫反应性（SPLI）和GABA的浓度进行了比较。海人酸（AA3）、quisqualic酸（AA2）和AMPA（AA2）导致所检测的所有四种神经化学标志物呈剂量依赖性降低，而N-甲基-D,L-天冬氨酸（AA1）和喹啉酸（AA1）则相对保留了SLI和NPYLI。在每种兴奋毒素导致GABA和SPLI均降低50%的剂量下，只有N-甲基-D,L-天冬氨酸和喹啉酸对SLI和NPYLI的浓度没有显著影响。通过使用NADPH-黄递酶神经元的组织化学染色结合尼氏染色或脑啡肽免疫组织化学染色，从组织学上证实了生长抑素-神经肽Y神经元的相对保留。N-甲基-D-天冬氨酸激动剂所致损伤导致NADPH-黄递酶神经元优先保留，而这些神经元比其他神经元更容易受到海人酸或AMPA的损伤。与其他神经元相比，胆碱乙酰转移酶神经元相对保留，这是由作用于所有三种谷氨酸受体亚型的药物所致。N-甲基-D,L-天冬氨酸损伤被MK-801阻断，而对quisqualic酸或海人酸损伤没有影响。用N-甲基-D-天冬氨酸（AA1）激动剂进行纹状体兴奋毒素损伤后，生长抑素-神经肽Y神经元的相对保留可能反映了这些神经元上AA1受体的缺乏。由于这些神经元在亨廷顿病中也被保留，作用于N-甲基-D-天冬氨酸（AA1）位点的兴奋毒素为这种疾病提供了一个改进的神经化学模型。
