Kalisch B E, Jhamandas K, Beninger R J, Boegman R J
Departments of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Brain Res. 1999 Jan 30;817(1-2):151-62. doi: 10.1016/s0006-8993(98)01254-2.
The present study was designed to examine the role of nitric oxide (NO) in quinolinic acid (QUIN)-induced depletion of rat striatal nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase and enkephalinergic neurons. Intrastriatal injection of QUIN produced a dose-dependent decrease in NADPH diaphorase and enkephalin positive cells, with cell loss being evident following the injection of 6 and 18 nmol QUIN, respectively. To evaluate the role of NO in QUIN-induced toxicity, animals were pretreated with the non-specific nitric oxide synthase (NOS) inhibitor, Nomega-nitro-l-arginine (l-NAME) or the selective neuronal NOS inhibitor, 7-nitro indazole (7-NI). l-NAME (2x250 mg/kg, i.p. 8 h apart) maximally inhibited striatal NOS activity by 85%, while 7-NI (50 mg/kg, i.p.) maximally inhibited striatal NOS activity by 60%. Pretreatment with l-NAME or 7-NI potentiated the loss of NADPH diaphorase neurons resulting from intrastriatal injection of low doses of QUIN (18 nmol). Neither NOS inhibitor had any effect on the loss of striatal NADPH diaphorase neurons induced by a higher dose of QUIN (24 nmol). In contrast, 7-NI partially prevented the QUIN (18 and 24 nmol)-induced loss of enkephalinergic neurons, while l-NAME had no effect. These results indicate that NO formation may play a role in QUIN-induced loss of enkephalinergic neurons, but not in the loss of NADPH diaphorase neurons.
本研究旨在探讨一氧化氮（NO）在喹啉酸（QUIN）诱导的大鼠纹状体烟酰胺腺嘌呤二核苷酸磷酸（NADPH）黄递酶和脑啡肽能神经元耗竭中的作用。纹状体内注射QUIN可使NADPH黄递酶和脑啡肽阳性细胞呈剂量依赖性减少，分别注射6 nmol和18 nmol QUIN后细胞损失明显。为评估NO在QUIN诱导的毒性中的作用，动物预先用非特异性一氧化氮合酶（NOS）抑制剂Nω-硝基-L-精氨酸（L-NAME）或选择性神经元NOS抑制剂7-硝基吲唑（7-NI）进行预处理。L-NAME（2×250 mg/kg，腹腔注射，间隔8小时）最大程度地抑制纹状体NOS活性达85%，而7-NI（50 mg/kg，腹腔注射）最大程度地抑制纹状体NOS活性达60%。用L-NAME或7-NI预处理可增强低剂量（18 nmol）纹状体内注射QUIN导致的NADPH黄递酶神经元损失。两种NOS抑制剂对高剂量（24 nmol）QUIN诱导的纹状体NADPH黄递酶神经元损失均无影响。相反，7-NI部分预防了QUIN（18和24 nmol）诱导的脑啡肽能神经元损失，而L-NAME则无作用。这些结果表明，NO的形成可能在QUIN诱导的脑啡肽能神经元损失中起作用，但在NADPH黄递酶神经元损失中不起作用。
