Anticonvulsant effects of the selective melatonin receptor agonist ramelteon.
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.
Fenoglio-Simeone
Kristina
K
Creighton University School of Medicine, Omaha, NE, USA.
Mazarati
Andrey
A
Sefidvash-Hockley
Sepideh
S
Shin
Don
D
Wilke
Julianne
J
Milligan
Heather
H
Sankar
Raman
R
Rho
Jong M
JM
Maganti
Rama
R
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
D000927:Anticonvulsants; D007192:Indenes; C496947:Kcna1 protein, mouse; D044094:Receptors, Melatonin; D051662:Kv1.1 Potassium Channel; C495910:ramelteon