Payandemehr Borna, Rahimian Reza, Gooshe Maziar, Bahremand Arash, Gholizadeh Ramtin, Berijani Sina, Ahmadi-Dastgerdi Mohammad, Aminizade Mehdi, Sarreshte-Dari Ali, Dianati Vahid, Amanlou Massoud, Dehpour Ahmad Reza
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Epilepsy Behav. 2014 May;34:99-104. doi: 10.1016/j.yebeh.2014.03.020. Epub 2014 Apr 14.
Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.
沙利度胺是一种古老的谷氨酸衍生物，最初用作镇静药物，但由于致畸性发生率高而退出市场。最近，由于其对包括神经退行性疾病在内的多种疾病具有潜在的对抗作用，它又重新出现。除了止吐和催眠作用外，沙利度胺在实验环境中还具有一些抗惊厥特性。然而，沙利度胺作用的潜在机制尚未完全明确。一些研究表明，沙利度胺可通过影响不同靶点，包括细胞因子（如肿瘤坏死因子α）、神经递质和一氧化氮（NO），发挥免疫调节或神经调节特性。在这方面，我们使用戊四氮（PTZ）诱导雄性NMRI小鼠阵挛性惊厥的模型，来研究沙利度胺的抗惊厥作用是否通过调节L-精氨酸-一氧化氮途径而受到影响。注射单剂量有效剂量的沙利度胺（10mg/kg，腹腔注射或更高剂量）可显著提高惊厥阈值（P<0.05）。一方面，用低剂量且本身无效的L-精氨酸[NO前体]（10、30和60mg/kg）预处理可阻止沙利度胺的抗惊厥作用。另一方面，一氧化氮合酶抑制剂[L-NAME和7-NI]在相对低剂量时可增强亚有效剂量沙利度胺（1和5mg/kg，腹腔注射）的抗惊厥作用。同时，几个剂量的氨基胍[一种诱导型一氧化氮合酶抑制剂]（20、50和100mg/kg）未能显著改变沙利度胺的抗惊厥作用。总之，我们的研究结果表明，L-精氨酸-一氧化氮途径可能参与沙利度胺的抗惊厥特性，并且组成型nNOS在报道的神经保护特性中起突出作用。
