Vanaja Paul, Ekambaram P
Department of Pharmacology and Environmental Toxicology, Dr. A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai 600 113, Taramani, India.
Pharmacol Biochem Behav. 2004 Jan;77(1):1-8. doi: 10.1016/j.pbb.2003.08.020.
In this study, the dose (50, 100, 150, and 200 mg/kg)- and time (30 and 60 min)- related effects of 7-nitroindazole (7-NI), a neuronal specific inhibitor of nitric oxide synthase (NOS) were tested on picrotoxin (5 mg/kg)-induced convulsions and memory formation in rats. The changes produced by these doses of 7-NI were determined on NOS activity and nitric oxide (NO) concentration in the brain. The effects of 7-NI were tested in animals pretreated (30 min) with L-arginine (500 and 1000 mg/kg). 7-NI, at 50 and 100 mg/kg, did not produce significant changes in NOS activity and NO concentration in the brain and memory formation. However, the convulsant action of picrotoxin was inhibited in a dose-dependent manner in these animals. A time-dependent decrease in the activity of NOS and the concentration of NO, a promotion of picrotoxin-induced convulsions, and an impairment of memory were found in animals treated with 150 and 200 mg/kg of 7-NI. The larger and not the smaller dose of L-arginine raised the concentration of NO, inhibited picrotoxin-induced convulsions and promoted memory process. Either dose of L-arginine failed to prevent 50 and 100 mg/kg of 7-NI from inhibiting convulsions. The effects of the larger doses of 7-NI (150 and 200 mg/kg) were effectively prevented by the increase of NO and not the ineffective dose of L-arginine. These results suggest that 7-NI (50 and 100 mg/kg) decreases convulsions by a nonspecific mechanism and that an inhibition of NOS by the larger doses of it (150 and 200 mg/kg) results in proconvulsant action and memory impairment. The data further show that the margin between the protective and proconvulsant doses of 7-NI is relatively narrow. These results have been taken together with the earlier reports that 7-NI produces learning impairment and fails to increase the anticonvulsant effect of traditional antiepileptic agents on experimentally induced convulsions to conclude that 7-NI can never emerge as an anticonvulsant agent for clinical use.
在本研究中，测试了神经元特异性一氧化氮合酶（NOS）抑制剂7-硝基吲唑（7-NI）在剂量（50、100、150和200mg/kg）和时间（30和60分钟）方面对大鼠匹鲁卡品（5mg/kg）诱导的惊厥和记忆形成的影响。测定了这些剂量的7-NI对大脑中NOS活性和一氧化氮（NO）浓度产生的变化。在预先用L-精氨酸（500和1000mg/kg）预处理（30分钟）的动物中测试了7-NI的作用。50和100mg/kg的7-NI对大脑中的NOS活性、NO浓度和记忆形成未产生显著变化。然而，在这些动物中，匹鲁卡品的惊厥作用以剂量依赖性方式受到抑制。在接受150和200mg/kg 7-NI治疗的动物中，发现NOS活性和NO浓度随时间下降，匹鲁卡品诱导的惊厥加剧，以及记忆受损。较大剂量而非较小剂量的L-精氨酸提高了NO浓度，抑制了匹鲁卡品诱导的惊厥并促进了记忆过程。任一剂量的L-精氨酸均未能阻止50和100mg/kg的7-NI抑制惊厥。较大剂量的7-NI（150和200mg/kg）的作用可通过增加NO有效预防，而不是无效剂量的L-精氨酸。这些结果表明，7-NI（50和100mg/kg）通过非特异性机制减少惊厥，而较大剂量（150和200mg/kg）对NOS的抑制导致惊厥作用增强和记忆受损。数据进一步表明，7-NI的保护剂量和惊厥剂量之间的差距相对较窄。这些结果与早期报告一致，即7-NI会导致学习障碍，并且不能增强传统抗癫痫药物对实验性诱导惊厥的抗惊厥作用，从而得出结论：7-NI永远无法成为临床使用的抗惊厥药物。
