Anticonvulsant Action Of Clonazepam Research Articles

Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model

The aim of this study was to characterize the influence of WIN 55,212-2 (WIN—a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P < 0.001), phenobarbital (P < 0.05) and valproate (P < 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/kg) significantly potentiated the anticonvulsant action of clonazepam (P < 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test.

Role of neurosteroids in the anticonvulsant activity of midazolam

Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA(A) receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA(A) receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test. Midazolam (500-5000 µg·kg(-1) , i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α-reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11β-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg(-1) ) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO. Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO.

Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in miceA

The aim of this study was to assess the influence of agmatine (an endogenous neuromodulator/neurotransmitter in the brain) on the protective action of numerous classical and second-generation antiepileptic drugs (clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, vigabatrin, and valproate) in the mouse pentetrazole-induced clonic seizure model.The results indicate that agmatine (up to 100mg/kg, ip, 45min before the test) did not alter the threshold for pentetrazole-induced clonic seizures in mice. However, agmatine (100mg/kg, ip) significantly attenuated the anticonvulsant effects of vigabatrin against pentetrazole-induced clonic seizures by elevating the ED50 value of vigabatrin from 517.5 to 790.3mg/kg (p<0.01). In contrast, agmatine at a dose of 50mg/kg did not significantly affect the anticonvulsant action of vigabatrin, although a reduction in the ED50 value of the antiepileptic drug from 517.5 to 629.1mg/kg was documented. Moreover, agmatine at doses of 50 and 100mg/kg (ip) had no significant impact on the anticonvulsant action of clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, or valproate in pentetrazole-induced seizures in mice.In conclusion, the combination of agmatine with vigabatrin seems to be unfavorable due to the reduction of the anticonvulsant effect of vigabatrin after concomitant administration of agmatine in the pentetrazole-induced seizure model. Therefore, the utmost caution is advised when combining agmatine with vigabatrin in further clinical settings.