Beal M F, Kowall N W, Swartz K J, Ferrante R J, Martin J B
Neurology Service, Massachusetts General Hospital, Boston 02114.
J Neurosci. 1988 Oct;8(10):3901-8. doi: 10.1523/JNEUROSCI.08-10-03901.1988.
Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian brain that reproduces many of the histologic and neurochemical features of Huntington's disease (HD). In the present study we have examined the ability of a variety of systemically administered compounds to modify striatal QA neurotoxicity. Lesions were assessed by measurements of the intrinsic striatal neurotransmitters substance P, somatostatin, neuropeptide Y, and GABA. Histologic examination was performed with Nissl stains. The antioxidants ascorbic acid, beta-carotene, and alpha-tocopherol administered s.c. for 3 d prior to striatal QA lesions had no significant effect. Other drugs were administered i.p. 1/2 hr prior to QA striatal lesions. The following were ineffective in blocking QA excitotoxicity: allopurinol, 50 and 100 mg/kg; ketamine, 75 mg/kg; nimodipine, 2.4, and 10 mg/kg; baclofen, 10 mg/kg; 2-amino-5-phosphonovalerate, 50 mg/kg; and 2-amino-7-phosphonoheptanoate, 50 mg/kg. Oral taurine administration for 4 weeks resulted in significantly increased levels of brain taurine but had no significant effect in blocking QA neurotoxicity. Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 resulted in a dose-responsive protection against QA toxicity, with complete block at a dose of 4 mg/kg. If the pathogenesis of HD involves QA or another excitotoxin acting at the NMDA receptor, it is possible that MK-801 could retard the degenerative process.
喹啉酸（QA）是哺乳动物大脑中存在的一种内源性兴奋性毒素，它可重现亨廷顿舞蹈病（HD）的许多组织学和神经化学特征。在本研究中，我们检测了多种全身给药化合物改变纹状体QA神经毒性的能力。通过测量纹状体内源性神经递质P物质、生长抑素、神经肽Y和GABA来评估损伤情况。用尼氏染色法进行组织学检查。在纹状体QA损伤前3天皮下注射抗氧化剂抗坏血酸、β-胡萝卜素和α-生育酚，未产生显著影响。其他药物在QA纹状体损伤前半小时腹腔注射。以下药物在阻断QA兴奋性毒性方面无效：别嘌呤醇，50和100mg/kg；氯胺酮，75mg/kg；尼莫地平，2.4和10mg/kg；巴氯芬，10mg/kg；2-氨基-5-磷酸戊酸，50mg/kg；以及2-氨基-7-磷酸庚酸，50mg/kg。口服牛磺酸4周可使脑内牛磺酸水平显著升高，但在阻断QA神经毒性方面无显著作用。全身给予非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂MK-801可产生剂量依赖性的QA毒性保护作用，在剂量为4mg/kg时可完全阻断。如果HD的发病机制涉及QA或另一种作用于NMDA受体的兴奋性毒素，那么MK-801有可能延缓退行性病变过程。
