Beal M F, Ferrante R J, Swartz K J, Kowall N W
Neurochemistry and Experimental Neuropathology Laboratories, Massachusetts General Hospital, Boston 02114.
J Neurosci. 1991 Jun;11(6):1649-59. doi: 10.1523/JNEUROSCI.11-06-01649.1991.
We previously found a relative sparing of somatostatin and neuropeptide Y neurons 1 week after producing striatal lesions with NMDA receptor agonists. These results are similar to postmortem findings in Huntington's disease (HD), though in this illness there are two- to threefold increases in striatal somatostatin and neuropeptide Y concentrations, which may be due to striatal atrophy. In the present study, we examined the effects of striatal excitotoxin lesions at 6 months and 1 yr, because these lesions exhibit striatal shrinkage and atrophy similar to that occurring in HD striatum. At 6 months and 1 yr, lesions with the NMDA receptor agonist quinolinic acid (QA) resulted in significant increases (up to twofold) in concentrations of somatostatin and neuropeptide Y immunoreactivity, while concentrations of GABA, substance P immunoreactivity, and ChAT activity were significantly reduced. In contrast, somatostatin and neuropeptide Y concentrations did not increase 6 months after kainic acid (KA) or alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) lesions. At both 6 months and 1 yr, QA lesions showed striking sparing of NADPH-diaphorase neurons as compared with both AMPA and KA lesions, neither of which showed preferential sparing of these neurons. Long-term QA lesions also resulted in significant increases in concentrations of both 5-HT and 5-hydroxyindoleacetic acid (HIAA), similar to findings in HD. Chronic QA lesions therefore closely resemble the neurochemical features of HD, because they result in increases in somatostatin and neuropeptide Y and in 5-HT and HIAA. These findings strengthen the possibility that an NMDA receptor-mediated excitotoxic process could play a role in the pathogenesis of HD.
我们先前发现，在用NMDA受体激动剂造成纹状体损伤1周后，生长抑素和神经肽Y神经元相对未受影响。这些结果与亨廷顿舞蹈病（HD）的尸检结果相似，不过在这种疾病中，纹状体生长抑素和神经肽Y的浓度增加了两到三倍，这可能是由于纹状体萎缩所致。在本研究中，我们检测了6个月和1年时纹状体兴奋性毒素损伤的影响，因为这些损伤表现出与HD纹状体中发生的情况类似的纹状体缩小和萎缩。在6个月和1年时，用NMDA受体激动剂喹啉酸（QA）造成的损伤导致生长抑素和神经肽Y免疫反应性浓度显著增加（高达两倍），而GABA、P物质免疫反应性和ChAT活性的浓度则显著降低。相比之下，在使用 kainic 酸（KA）或α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）造成损伤6个月后，生长抑素和神经肽Y的浓度并未增加。在6个月和1年时，与AMPA和KA损伤相比，QA损伤显示出NADPH-黄递酶神经元明显未受影响，而后两者均未显示出这些神经元的优先保留。长期QA损伤还导致5-羟色胺（5-HT）和5-羟吲哚乙酸（HIAA）的浓度显著增加，这与HD中的发现相似。因此，慢性QA损伤与HD的神经化学特征非常相似，因为它们导致生长抑素、神经肽Y以及5-HT和HIAA增加。这些发现强化了NMDA受体介导的兴奋性毒性过程可能在HD发病机制中起作用的可能性。
