Modafinil Antiepileptic Effect And Mechanism

Epilepsy is a common neurological disorder affecting adults and children around the world.It is characterized by hyperexcitability and hypersynchrony of neuronal networks.The underlying mechanisms for this pathological synchrony are yet mostly hypothetical.Nevertheless,a focus of interest is the hypothesis that disruption of electroencephalographically(EEG)synchronized epileptiform discharges may be a possible therapy for epilepsy.The hypothesis that EEG desynchronization could inhibit epilepsy has attracted much more attention at present.Desynchronization may play an important role in the antiepileptic mechanism of drugs that influence sleep structure.This possibility led us to postulate that central nervous system stimulants with desynchronization activity may have antiepileptic effect.We chose modafinil as a stimulant,which is a potent wake-promoting drug used in patients with excessive sleepiness associated with a variety of sleep disorders including narcolepsy.In the present study,to clarify the role of EEG desynchronization on epilepsy, we investigated the effects of modafinil on epilepsy,and clarified the receptors involved in the suppression of seizure caused by maximal electroshock(MES)model, pentylenetetrazol(PTZ)-induced acute convulsion and kindling models.The EEG power density analysis method was applied to determine EEG desynchronization action of modafinil.The expression of adrenergicα_1A,α_1B,α_1Dreceptor mRNA in cortex of mice was quantified by real-time RT-PCR.Part 1;Research on the antiepileptic effect of modafinil and receptor mechanisms. The present study was to investigate the antiepileptic effect of modafinil and receptor mechanism involved in it.The antiepileptic effect of modafinil was tested in MES, PTZ-induced acute convulsion and kindling models.The receptors involved in the antiepileptic effect of modafinil was determined by adrenergicα₁,α₂,dopaminergic D₁,D₂ and histamine H₁ receptor antagonists.Modafinil administration at 22.5,45, and 90 mg/kg significantly decreased the incidence of MES-induced tonic hind-leg extension(THE)at 0.5 h to 50%,30%,and 10%,respectively.Modaflnil protected against PTZ-indueed convulsive behaviors in a dose-dependent manner.In the vehicle-treated mice,the latency of myoclonic jerk and generalized clonus was 87±5 and 140±9 sec,respectively.When adminerstrated at a dose of 22.5,45 or 90 mg/kg, modafinil significantly prolonged the latency to 112±3,183±16,and 191±19 sec respectively,for myoclonic jerk,and to 986±307,1669±130,and 1683±116 sec, respectively,for generalized clonus.The mean seizure stage of the vehicle-treated group was 4.3±0.2.Modafinil at 22.5,45 and 90 mg/kg dose-dependently decreased the mean seizure stages to 3.4±0.3,2.6±0.2,2.5±0.3,respectively;The antiepileptic effect in both MES and PTZ kindling models was antagonized by adrenergicα₁ receptor antagonist terazosin,but not by adrenergicα₂ receptor antagonist yohimbine or by dopaminergic receptor antagonists,SCH-23390(for D₁ receptor)and haloperidol(for D₂ receptor).Pyrilamine,a histaminergic H₁ receptor antagonist,counteracted the anti-epileptic action of modafinil in the PTZ induced-kindling model,but not in the MES seizure model.However,modafinil administration at 180,360 mg/kg obviously increased PTZ-induced convulsive behaviors in PTZ induced kindling and acute convulsion models.The results indicate that low-dose modafinil exerts potent antiepileptic effect via adrenergicα₁ and histamine H₁ receptors.Part 2;Research on the EEG desynchronization action of modafinil and receptor mechanism.A dominant electrophysiological characteristic of epilepsy is the loss of desynchronized EEG activity and shift toward low-frequency EEG synchronization. In mice,similar EEG changes resulted from administering the anti-cholinergic scopolamine(1 mg/kg)and the monoamine depletor reserpine(10 mg/kg);amplitude increases between 0～20 Hz,with the delta(0～4 Hz)and theta(4～8 Hz)bands affected severely.Modafinil(22.5～360 mg/kg)was given to investigate the desynchronization effect in the synchoronized mice.Adrenergicα₁ and histamine H₁ receptor antagonists were pretreated to evaluate which receptor mediates the desynchronization of modafinil.Modafinil given at 22.5,45,and 90 mg/kg significantly reversed these EEG changes in a dose-dependent manner,with a prominent decrease in delta bands.The absolute delta power densitity of modafinil at 22.5,45 and 90 mg/kg was decreased to 44%,35%,and 28%compared with the value of the group after treatment with reserpine and scopolamine treated group, respectivly.Pretreated with adrenergicα₁ receptor antagonist terazosin(0.5,1 mg/kg) dose-dependently suppressed the EEG desynchronization of modafinil in all frequency bands from 0 to 20 Hz,but pretreatment with histaminergic H₁ receptor antagonist pyrilamine(1 mg/kg)did affect it.These results suggested that the modafinil have potent desynchronization action,and which mediated by adrenergicα₁ receptor.Part 3;Effect of modafinil on the expression of adrenergicα_1A,α_1B,α_1Dreceptor mRNA in cortex.Adrenergicα₁ receptor subtypes play an important role in the development of the central nervous system and pathological conditions,such as epilepsy.The antiepileptic effect of modafinil was mediated by adrenergicα₁ receptor.In order to determine which one of adrenergicα_1A,α_1Bandα_1Dresponsible for the antiepileptic effect of modafinil,the mRNA expression of them was assessed by real-time RT-PCR. Adrenergicα_1AmRNA level significantly increased at 0.5 h after modafinil injection compared with vehicle in cortex,but it did not show significant influence on the expression of adrenergicα_1B,α_1DmRNA.These data suggest that adrenergicα_1Awas up regulated after given modafinil 90 mg/kg,activation of the adrenergicα_1A signaling system might be involved in the process of antiepileptic effect of modafinil.Summary;1.Low-dose modafinil exerts potent antiepileptic effect,but high-dose aggravates epilepsy.2.The anti-epileptic effect of modafinil was mediated by adrenergicα₁ and histamine H₁ receptors.3.EEG desynchronization and the activation of adrenergic system contributed to the antiepileptic effects of modafinil.4.Selective increase in adrenergicα₁-receptor subunits may play a role in the antiepileptic effect of modafinil.