Borowicz K K, Kleinrok Z, Czuczwar S J
Department of Pharmacology and Toxicology, Medical University, Lublin, Poland.
Epilepsia. 2000 Sep;41(9):1112-8. doi: 10.1111/j.1528-1157.2000.tb00316.x.
The objective of this study was to evaluate the interaction of the preferential brain nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), with conventional antiepileptic drugs (AEDs) against amygdala-kindled seizures in rats.
Experiments were performed on fully kindled rats. Adverse effects were evaluated with the rotorod test, which assesses motor coordination, and the passive-avoidance task, which assesses memory. Plasma levels of AEDs were measured by immunofluorescence.
7-NI (up to 100 mg/kg) failed to modify seizure parameters. However, it reduced the severity and duration of kindled seizures when coadministered with otherwise ineffective doses of carbamazepine (CBZ) (10-20 mg/kg) or phenobarbital (PB) (20 mg/kg). Combinations of 7-NI with valproate (VPA), diphenylhydantoin (DPH), or clonazepam (CLO) were not protective. L-Arginine (500 mg/kg) did not reverse the seizure-suppressing interactions between 7-NI and the conventional AEDs. The combinations of 7-NI and CBZ or PB did not impair performance in the rotorod test. Coadministration of 7-NI with CBZ did not affect long-term memory, and 7-NI given with PB didn't affect the mnemonic effect of PB. Finally, 7-NI did not affect the free plasma levels of CBZ or PB.
Pharmacokinetic interactions do not seem to account for the anticonvulsant effects of 7-NI combined with CBZ or PB. Central nitric oxide (NO) is possibly not involved in the synergism between 7-NI and these AEDs.
本研究的目的是评估选择性脑一氧化氮合酶（NOS）抑制剂7-硝基吲唑（7-NI）与传统抗癫痫药物（AEDs）联合使用对大鼠杏仁核点燃癫痫发作的相互作用。
在完全点燃的大鼠上进行实验。通过旋转棒试验评估运动协调性，通过被动回避任务评估记忆力，以此来评估不良反应。采用免疫荧光法测定AEDs的血浆水平。
7-NI（高达100mg/kg）未能改变癫痫发作参数。然而，当与无效剂量的卡马西平（CBZ）（10-20mg/kg）或苯巴比妥（PB）（20mg/kg）联合使用时，它可降低点燃癫痫发作的严重程度和持续时间。7-NI与丙戊酸（VPA）、苯妥英（DPH）或氯硝西泮（CLO）联合使用无保护作用。L-精氨酸（500mg/kg）不能逆转7-NI与传统AEDs之间的癫痫抑制相互作用。7-NI与CBZ或PB联合使用不影响旋转棒试验中的表现。7-NI与CBZ联合给药不影响长期记忆，7-NI与PB联合给药不影响PB的记忆效果。最后，7-NI不影响CBZ或PB的游离血浆水平。
药代动力学相互作用似乎不能解释7-NI与CBZ或PB联合使用的抗惊厥作用。中枢一氧化氮（NO）可能不参与7-NI与这些AEDs之间协同作用。
