Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic alpha1 and histaminergic H1 receptors in mice.
Epilepsy is characterized by neuronal hyperexcitability and hypersynchronization. Disruption of electroencephalographically (EEG) synchronized epileptiform discharges may be a possible therapy for epilepsy. In the present study, to clarify the role of EEG desynchronization on epilepsy, we investigated the effect of modafinil, a potent wake-promoting substance with EEG desynchronization activity, on epilepsy in mice and clarified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) kindling models. Modafinil given at 22.5, 45, and 90 mg/kg, i.p. significantly decreased the incidence of tonic hindleg extension in MES seizure models, and protected against PTZ-induced convulsive behaviors in a dose-dependent manner. In addition, modafinil at 180 mg/kg exerted an antiepileptic effect in the MES model; however, at the same dosage it increased the seizure stage in the PTZ-kindling model. The antiepileptic effect in both MES and PTZ models was antagonized by the adrenergic alpha(1) receptor antagonist terazosin, but not by the adrenergic alpha(2) receptor antagonist yohimbine or by dopaminergic receptor antagonists, SCH-23390 (for D(1) receptors) and haloperidol (for D(2) ones). Pyrilamine, a histaminergic H(1) receptor antagonist, counteracted the antiepileptic action of modafinil in the PTZ induced-kindling model, but not in the MES seizure model. Taken together, the present findings indicate that modafinil exerted its antiepileptic effect via adrenergic alpha(1) and histaminergic H(1) receptors, and might be of potential use in the treatment of epilepsy.
Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
C R
CR
Chen
W M
WM
Qu
M H
MH
Qiu
X H
XH
Xu
M H
MH
Yao
Y
Y
Urade
Z L
ZL
Huang
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004597:Electroshock; D004827:Epilepsy / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000077408:Modafinil; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000209:etiology / Q000517:prevention & control
D001559:Benzhydryl Compounds; D018696:Neuroprotective Agents; D000077408:Modafinil; D010433:Pentylenetetrazole