Yahyavi-Firouz-Abadi Noushin, Tahsili-Fahadan Pouya, Riazi Kiarash, Ghahremani Mohammad Hossein, Dehpour Ahmad Reza
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Epilepsy Res. 2006 Feb;68(2):103-13. doi: 10.1016/j.eplepsyres.2005.09.057. Epub 2006 Jan 10.
Melatonin, the major hormone produced by the pineal gland, is shown to have anticonvulsant effects. Nitric oxide (NO) is a known mediator in seizure susceptibility modulation. In the present study, the involvement of NO pathway in the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced clonic seizures was investigated in mice. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) significantly increased the clonic seizure threshold induced by intravenous administration of PTZ. This effect was observed as soon as 1 min after injection and lasted for 30 min with a peak effect at 3 min after melatonin administration. Combination of per se non-effective doses of melatonin (10 and 20 mg/kg) and nitric oxide synthase (NOS) substrate L-arginine (30, 60 mg/kg) showed a significant anticonvulsant activity. This effect was reversed by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for melatonin effect. Pretreatment with L-NAME (30 mg/kg) and N(G)-nitro-L-arginine (L-NNA, 10 mg/kg) inhibited the anticonvulsant property of melatonin (40 and 80 mg/kg) and melatonin 40 mg/kg, respectively. Specific inducible NOS (iNOS) inhibitor aminoguanidine (100 and 300 mg/kg) did not affect the anticonvulsant effect of melatonin, excluding the role of iNOS in this phenomenon, while pretreatment of with 7-NI (50 mg/kg), a preferential neuronal NOS inhibitor, reversed this effect. The present data show an anticonvulsant effect for melatonin in i.v. PTZ seizure paradigm, which may be mediated via NO/L-arginine pathway by constitutively expressed NOS.
褪黑素是松果体产生的主要激素，已显示具有抗惊厥作用。一氧化氮（NO）是已知的癫痫易感性调节介质。在本研究中，研究了NO途径在褪黑素对戊四氮（PTZ）诱导的阵挛性癫痫的抗惊厥作用中的参与情况。急性腹腔注射褪黑素（40和80mg/kg）显著提高了静脉注射PTZ诱导的阵挛性癫痫阈值。该效应在注射后1分钟即可观察到，并持续30分钟，在褪黑素给药后3分钟达到峰值效应。本身无效剂量的褪黑素（10和20mg/kg）与一氧化氮合酶（NOS）底物L-精氨酸（30、60mg/kg）联合使用显示出显著的抗惊厥活性。NOS抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME，30mg/kg）可逆转该效应，这意味着褪黑素的作用机制依赖于NO。用L-NAME（30mg/kg）和N（G）-硝基-L-精氨酸（L-NNA，10mg/kg）预处理分别抑制了褪黑素（40和80mg/kg）和40mg/kg褪黑素的抗惊厥特性。特异性诱导型NOS（iNOS）抑制剂氨基胍（100和300mg/kg）不影响褪黑素的抗惊厥作用，排除了iNOS在该现象中的作用，而用优先作用于神经元的NOS抑制剂7-NI（50mg/kg）预处理可逆转该效应。目前的数据表明，褪黑素在静脉注射PTZ癫痫模型中具有抗惊厥作用，这可能是通过组成型表达的NOS经由NO/L-精氨酸途径介导的。
