title: Anticonvulsant effects of the selective melatonin receptor agonist ramelteon.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Creighton University School of Medicine, Omaha, NE, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Fenoglio-Simeone
authors.forename: Andrey
authors.initials: A
authors.lastname: Mazarati
authors.forename: Sepideh
authors.initials: S
authors.lastname: Sefidvash-Hockley
authors.forename: Don
authors.initials: D
authors.lastname: Shin
authors.forename: Julianne
authors.initials: J
authors.lastname: Wilke
authors.forename: Heather
authors.initials: H
authors.lastname: Milligan
authors.forename: Raman
authors.initials: R
authors.lastname: Sankar
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
authors.forename: Rama
authors.initials: R
authors.lastname: Maganti
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D004567:Electrodes, Implanted; D004569:Electroencephalography; D006624:Hippocampus / Q000502:physiology; D007192:Indenes / Q000627:therapeutic use*; D007696:Kindling, Neurologic / Q000187:drug effects; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000819:agonists*; D012640:Seizures / Q000517:prevention & control
chemical_list: D000927:Anticonvulsants; D007192:Indenes; C496947:Kcna1 protein, mouse; D044094:Receptors, Melatonin; D051662:Kv1.1 Potassium Channel; C495910:ramelteon