Tehran University of Medical Sciences, Faculty of Pharmacy, Pharmacology and Toxicology, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2017 Nov 15;815:454-461. doi: 10.1016/j.ejphar.2017.10.002. Epub 2017 Oct 4.
This study aims to investigate the role of zolpidem in lithium-pilocarpine induced status epilepticus (SE) and probable mechanisms involved in seizure threshold alteration. In the present study, lithium chloride (127mg/kg) was administered 20h prior to pilocarpine (60mg/kg) to induce SE in adult male Wistar rats. Different doses of zolpidem (0.1, 1, 2, 5, 10mg/kg) were injected 30min before pilocarpine administration. Furthermore, to find out whether nitric oxide (NO) plays a role in the observed effect, L-arginine and L-NAME were injected 15min before zolpidem. Afterward, we identified the particular NO isoform mediating the effect of zolpidem by injecting aminoguanidine (AG) and 7-Nitroindazole (7-NI) 15min prior to zolpidem. Moreover, in both 6 and 24h after pilocarpine injection, experimental groups underwent hippocampectomy to evaluate cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes expression by quantitative reverse transcription-PCR (qRT-PCR). Pre-treatment with zolpidem significantly prevented the onset of SE in a dose-dependent manner. AG and L-NAME significantly potentiated the anticonvulsant effect of zolpidem while L-arginine inverted this effect. Our qRT-PCR exerted that there was a continuous elevation of iNOS and COX-2 genes expression over 6 and 24h after pilocarpine administration in SE and L-arginine+Zolpidem groups while in AG/L-NAME+Zolpidem and zolpidem groups this upregulation was prevented. Our study indicates that zolpidem prevents the onset of SE through inhibition of iNOS/COX-2 genes upregulation following lithium-pilocarpine administration. Consistent with our results, we suggest that iNOS activation could be probably upstream of COX-2 gene expression.
本研究旨在探讨唑吡坦在锂-匹罗卡品诱导的癫痫持续状态（SE）中的作用及可能涉及的癫痫发作阈改变的机制。在本研究中，在给予匹罗卡品（60mg/kg）之前 20 小时给予氯化锂（127mg/kg）以诱导成年雄性 Wistar 大鼠 SE。在给予匹罗卡品前 30 分钟给予不同剂量的唑吡坦（0.1、1、2、5、10mg/kg）。此外，为了确定一氧化氮（NO）是否在观察到的效应中起作用，在给予唑吡坦前 15 分钟给予 L-精氨酸和 L-NAME。之后，我们通过在给予唑吡坦前 15 分钟给予氨基胍（AG）和 7-硝基吲唑（7-NI）来鉴定介导唑吡坦作用的特定 NO 同工型。此外，在给予匹罗卡品后 6 和 24 小时，实验组进行海马切除术，通过定量逆转录-PCR（qRT-PCR）评估环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）基因的表达。唑吡坦预处理以剂量依赖性方式显著预防 SE 的发作。AG 和 L-NAME 显著增强唑吡坦的抗惊厥作用，而 L-精氨酸则反转了这种作用。我们的 qRT-PCR 表明，在 SE 和 L-精氨酸+唑吡坦组中，在给予匹罗卡品后 6 和 24 小时，iNOS 和 COX-2 基因表达持续升高，而在 AG/L-NAME+唑吡坦和唑吡坦组中，这种上调被阻止。我们的研究表明，唑吡坦通过抑制锂-匹罗卡品给药后 iNOS/COX-2 基因的上调来预防 SE 的发作。与我们的结果一致，我们认为 iNOS 激活可能是 COX-2 基因表达的上游。
