- 作者：Kristina Fenoglio-Simeone ; Andrey Mazarati ; Sepideh Sefidvash-Hockley ; Don Shin ; Julianne Wilke ; Heather Milligan ; Raman Sankar ; Jong M. Rho ; Rama Maganti
- 关键词：Ramelteon ; Melatonin ; Melatonin receptor ; Epilepsy ; Circadian rhythms
- 刊名：Epilepsy & Behavior
- 出版年：2009
- 出版时间：September 2009
- 年：2009
- 卷：16
- 期：1
- 页码：52-57
- 全文大小：289 K
ObjectiveThe 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.Methods
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.
Results
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.
Conclusions
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.