Role of neuronal nitric oxide in methamphetamine neurotoxicity and protection by nNOS inhibitor
Role of neuronal nitric oxide in methamphetamine neurotoxicity and protection by nNOS inhibitor
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DOI：
10.1351/pac200072061001
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发表时间：
2000-06-01
影响因子：
1.8
通讯作者：
Ali, SF
中科院分区：
文献类型：
--
作者：
Desaiah, D;Reddy, SLN;Ali, SF
甲基苯丙胺（METH）是一种有效的精神兴奋剂，已知会产生神经毒性。多巴胺能通路对甲基苯丙胺特别敏感。最近的研究表明，7-硝基吲唑（7-NI），神经元型一氧化氮合酶（nNOS）的选择性抑制剂，提供保护，对METH神经毒性在体外和体内。本研究进行，以确定nNOS活性在不同区域的年轻成年雄性Sprague-Dawley大鼠用不同剂量的METH治疗的脑。在处死大鼠后24 h，对大鼠腹腔注射5、10、20和40 mg/kg，并快速解剖脑区（海马、额叶皮质和小脑）。制备胞质组分，并使用H-3-瓜氨酸测定法测定nNOS活性。结果表明，METH处理的大鼠的所有三个脑区的nNOS活性均显著增加。增加呈剂量依赖性，最大值为对照值的40-100%。在注射METH之前30分钟用7-NI处理的大鼠提供了针对毒性的保护，并且还显示出nNOS活性的降低。已知nNOS的激活增加NO的合成，其参与包括儿茶酚胺能系统的多种神经递质通路的调节。用选择性nNOS抑制剂7-NI预处理减少METH诱导的NO产生，提供了对METH神经毒性的保护。
Methamphetamine (METH) is a potent psychostimulant known to produce neurotoxicity. The dopaminergic pathway is particularly sensitive to METH. Recent studies showed that 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), provided protection against METH neurotoxicity both in vitro and in vivo. The present studies were conducted to determine the nNOS activity in various regions of the brain of young adult male Sprague-Dawley rats treated with different doses of METH. Rats were injected ip with 5, 10, 20, and 40 mg/kg and 24 h after the rats were sacrificed and the brain regions (hippocampus, frontal cortex, and cerebellum) were quickly dissected. The cytosolic fractions were prepared, and the nNOS activity was determined using the H-3-citrulline assay. The results showed that nNOS activity was significantly increased in all three brain regions of rats treated with METH. The increase was dose dependent reaching a maximum of 40-100% over the control values. Rats treated with 7-NI 30 min prior to METH injection provided protection against the toxicity and also showed a reduction of nNOS activity. The activation of nNOS is known to increase the synthesis of NO which is involved in the regulation of several neurotransmitter pathways including catecholaminergic system. Reducing the METH-induced production of NO by pretreatment with selective inhibitor of nNOS, 7-NI, provided protection against METH neurotoxicity.