Fenoglio-Simeone Kristina, Mazarati Andrey, Sefidvash-Hockley Sepideh, Shin Don, Wilke Julianne, Milligan Heather, Sankar Raman, Rho Jong M, Maganti Rama
Creighton University School of Medicine, Omaha, NE, USA.
Epilepsy Behav. 2009 Sep;16(1):52-7. doi: 10.1016/j.yebeh.2009.07.022. Epub 2009 Aug 13.
The endogenous hormone melatonin has previously been shown to exert anticonvulsant effects in a variety of experimental models. Accordingly, we asked whether ramelteon, a synthetic and selective melatonin receptor agonist, might also possess anticonvulsant and/or antiepileptogenic properties.
The effects of ramelteon (30 or 100 mg/kg intraperitoneally twice daily for 5 days) were evaluated in two animal models of epilepsy. In the rat rapid kindling model, baseline hippocampal afterdischarge properties, kindling progression, and hippocampal excitability in kindled animals were measured. Anti-ictogenic efficacy was assessed after acute administration in untreated kindled rats. In the spontaneously epileptic Kcna1-null mouse model, we determined seizure frequency and periodicity using continuous video/EEG monitoring over 72 hours. Further, circadian rest-activity rhythms in ramelteon-treated animals were studied with actigraphy.
In kindled animals, ramelteon reversed kindling-induced hippocampal excitability; however, it did not modify baseline afterdischarge properties, the progression and establishment of the kindled state in the rapid kindling model. However, in Kcna1-null mice, ramelteon (200 mg/kg/day) significantly attenuated seizure periodicity and frequency and improved circadian rest-activity rhythms compared with control animals.
The selective melatonin receptor agonist ramelteon possesses anticonvulsant properties in a chronic epilepsy model. Our findings provide further support for melatonin receptors being potential novel targets for anticonvulsant drug development.
内源性激素褪黑素先前已被证明在多种实验模型中具有抗惊厥作用。因此，我们探究了雷美替胺（一种合成的选择性褪黑素受体激动剂）是否也具有抗惊厥和/或抗癫痫发生的特性。
在两种癫痫动物模型中评估雷美替胺（30或100mg/kg腹腔注射，每日两次，共5天）的作用。在大鼠快速点燃模型中，测量基线海马放电后特性、点燃进程以及点燃动物的海马兴奋性。在未治疗的点燃大鼠急性给药后评估抗致痫疗效。在自发性癫痫Kcna1基因敲除小鼠模型中，我们通过连续72小时的视频/脑电图监测确定癫痫发作频率和周期性。此外，用活动记录仪研究雷美替胺治疗动物的昼夜休息-活动节律。
在点燃动物中，雷美替胺逆转了点燃诱导的海马兴奋性；然而，它并未改变基线放电后特性、快速点燃模型中点燃状态的进程和确立。但是，在Kcna1基因敲除小鼠中，与对照动物相比，雷美替胺（200mg/kg/天）显著减弱了癫痫发作的周期性和频率，并改善了昼夜休息-活动节律。
选择性褪黑素受体激动剂雷美替胺在慢性癫痫模型中具有抗惊厥特性。我们的研究结果为褪黑素受体作为抗惊厥药物开发的潜在新靶点提供了进一步支持。
