Moradi Farid, Eslami Faezeh, Rahimi Nastaran, Koohfar Amirhossein, Shayan Maryam, Maadani Mahshad, Ghasemi Mehdi, Dehpour Ahmad Reza
Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Epilepsy Behav. 2022 May;130:108649. doi: 10.1016/j.yebeh.2022.108649. Epub 2022 Mar 26.
Status epilepticus (SE) is a continuous episode of seizures which leads to hippocampal neurodegeneration, severe systemic inflammation, and extreme damage to the brain. Modafinil, a psychostimulant and wake-promoting agent, has exerted neuroprotective and anti-inflammatory effects in previous preclinical studies. The aim of this study was to assess effects of modafinil on the lithium-pilocarpine-induced SE rat model and to explore possible involvement of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) pathways in this regard.
Status epilepticus was provoked by injection of lithium chloride (127 mg/kg, intraperitoneally [i.p]) and pilocarpine (60 mg/kg, i.p.) in rats. Animals received different modafinil doses (50, 75, 100, and 150 mg/kg, i.p.) and SE scores were documented over 3 hours of duration. Moreover, the role of the nitrergic pathway in the effects of modafinil was evaluated by injection of the non-selective NO synthase (NOS) inhibitor L-N-Nitro arginine methyl ester (L-NAME, 10 mg/kg, i.p.), the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg, i.p.), and the selective inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) 15 min before saline/vehicle or modafinil. The ELISA method was used to quantify TNF-α and NO metabolite levels in the isolated hippocampus.
Modafinil at 100 mg/kg significantly decreased SE scores (P < 0.01). Pre-treatment with L-NAME, 7-nitroindazole, and aminoguanidine significantly reversed the anticonvulsive effects of modafinil. Status epilepticus-induced animals showed significantly higher NO metabolite and TNF-α levels in their hippocampal tissues, an effect that was reversed by modafinil (100 mg/kg, i.p.) treatment. Administration of NOS inhibitors resulted in excessive NO level reduction but an escalation of TNF-α level in modafinil-treated SE-animals.
Our study revealed anticonvulsive effects of modafinil in the lithium-pilocarpine-induced SE rat model via possible involvement of TNF-α and nitrergic pathways.
癫痫持续状态（SE）是一种持续性癫痫发作，可导致海马神经变性、严重的全身炎症反应以及对大脑的极端损害。莫达非尼是一种精神振奋剂和促醒药物，在先前的临床前研究中已发挥神经保护和抗炎作用。本研究的目的是评估莫达非尼对氯化锂-匹罗卡品诱导的SE大鼠模型的影响，并探讨肿瘤坏死因子-α（TNF-α）和一氧化氮（NO）途径在这方面可能的参与情况。
通过给大鼠腹腔注射氯化锂（127mg/kg）和匹罗卡品（60mg/kg）诱发癫痫持续状态。动物接受不同剂量的莫达非尼（50、75、100和150mg/kg，腹腔注射），并在3小时内记录SE评分。此外，在注射生理盐水/溶剂或莫达非尼前15分钟，通过注射非选择性一氧化氮合酶（NOS）抑制剂L-N-硝基精氨酸甲酯（L-NAME，10mg/kg，腹腔注射）、选择性神经元NOS抑制剂7-硝基吲唑（30mg/kg，腹腔注射）和选择性诱导型NOS抑制剂氨基胍（100mg/kg，腹腔注射）来评估硝化途径在莫达非尼作用中的作用。采用酶联免疫吸附测定（ELISA）法对分离海马中的TNF-α和NO代谢物水平进行定量。
100mg/kg的莫达非尼显著降低了SE评分（P<0.01）。用L-NAME、7-硝基吲唑和氨基胍预处理显著逆转了莫达非尼的抗惊厥作用。癫痫持续状态诱导的动物海马组织中NO代谢物和TNF-α水平显著升高，莫达非尼（100mg/kg，腹腔注射）治疗可逆转这一效应。给予NOS抑制剂导致莫达非尼治疗的SE动物中NO水平过度降低，但TNF-α水平升高。
我们的研究揭示了莫达非尼在氯化锂-匹罗卡品诱导的SE大鼠模型中的抗惊厥作用可能通过TNF-α和硝化途径介导。
