Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain
Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain
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DOI：
10.1016/s0006-8993(03)03034-8
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发表时间：
2003-08-15
期刊：
影响因子：
2.9
通讯作者：
Dettbarn, WD
中科院分区：
文献类型：
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作者：
Gupta, RC;Dettbarn, WD
先前使用自旋捕获剂N-叔丁基-α-苯基硝酮（PBN）和抗氧化剂维生素E的研究确定了自由基参与红藻氨酸（KA）诱导的神经毒性。在本研究中，我们研究了神经元型一氧化氮合酶（nNOS）抑制剂7-硝基吲唑（7-NI）的影响，以确定一氧化氮（NO）在KA诱导的癫痫持续状态（SE）引起的神经毒性中的可能作用。单次注射KA（15 mg/kg，s.c.）在40-45 min内诱导癫痫发作，进展至完全癫痫发作活动持续约3 h。在微波（头部聚焦）照射后，使用高效液相色谱法（HPLC）分析了大鼠大脑区域（皮质、杏仁核和海马）的高氯酸提取物中的瓜氨酸（NO的决定因素）和高能磷酸盐（HEP）及其代谢产物。KA诱导的癫痫发作产生了最大的增加NO（3至6倍）和减少HEP（ATP 45-51%和磷酸肌酸45-58%）KA注射后2小时在大脑区域测试。7-NI（50 mg/kg，i.p.）当单独给药时，瓜氨酸/NO水平降低（10-24%），而重复给药7-NI（间隔60分钟）使NO水平降低32- 49%。7-NI的应用都没有产生HEP水平或毒性的变化。在KA注射前30分钟用7-NI预处理，延迟癫痫发作15-20分钟，并显著防止NO的增加和HER的降低。重复施用7-NI，即KA注射前30分钟和KA注射后30分钟，通过延迟癫痫发作进一步增加保护，减弱NO的增加和HER的降低癫痫发作的神经毒性涉及受影响神经元中nNOS和能量消耗的激活。这种增加的能量消耗，加上NO诱导的线粒体功能障碍引起的能量产生减少，可能是KA毒性中神经元损伤的一个促成因素。(C)2003 Elsevier B. V.保留所有权利。
Previous studies using the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E established the involvement of free radicals in kainic acid (KA)-induced neurotoxicity. In the present study, we examined the effects of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) to establish a possible role of nitric oxide (NO) in the neurotoxicity caused by KA-induced status epilepticus (SE). A single injection of KA (15 mg/kg, s.c.) induced seizures within 40-45 min, progressing to full seizure activity lasting about 3 h. Following microwave (head-focused) irradiation, perchloric acid extracts of rat brain regions (cortex, amygdala, and hippocampus) were analyzed for citrulline (determinant of NO) and high-energy phosphates (HEP) and their metabolites using high-performance liquid chromatograph (HPLC). KA-induced seizures produced a maximum increase in NO (3- to 6-fold) and a decrease in HEP (ATP 45-51% and phosphocreatine 45-58%) 2 h after KA injection in brain regions tested. 7-NI (50 mg/kg, i.p.) when given alone, reduced citrulline/NO levels (10-24%), while repeat administration of 7-NI (60 min apart) reduced NO levels by 32-49%. Neither application of 7-NI produced changes in HEP levels or toxicity. Pretreatment with 7-NI 30 min before KA injection, delayed the onset of seizures by 15-20 min, and significantly prevented an increase in NO and a decrease in HER Repeat administration of 7-NI, i.e. 30 min before and 30 min after KA injection, further increased protection by the delayed onset of seizures, attenuating the increase in NO and the decrease in HER Neurotoxicity of seizures involves activation of nNOS and of energy consumption in affected neurons. This increased energy consumption, coupled with decreased energy production caused by NO-induced mitochondrial dysfunction, may be a contributing factor to neuronal injury in KA toxicity. (C) 2003 Elsevier B.V. All rights reserved.