Salvinorin A Does Not Affect Seizure Threshold in Mice

The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1–10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.

Effect of nobiletin on experimental model of epilepsy

BackgroundThe effects of nobiletin, a plant-derived flavonoid was examined against pentylenetetrazole (PTZ)-induced seizures. The study also aimed to assess whether nobiletin potentiated the effects of antiepileptic drug clonazepam (CZP).MethodsPTZ (92 mg/kg, subcutaneous) was used to induce seizures in mice. Treatment groups (n = 18/group) received nobiletin (12.5, 25, or 50 mg/kg) via oral gavage for 6 consecutive days and 45 min prior to PTZ injection. CZP (0.015-2.0 mg/kg) was administered 15 min prior to PTZ. Skeletal muscle strength was assessed by measuring grip strength and Chimney test was performed to study the motor performance in animals. TUNEL assay was done to study neuro-apoptosis. RT-PCR and Western blot analysis were performed for assessment of mRNA and protein expressions.ResultsNobiletin and CZP improved muscle strength and motor coordination and reduced seizure severity significantly. The administration of nobiletin and CZP, individually or in combination, downregulated seizure-induced increases in apoptotic cell count and apoptotic protein expression, modulated the expression of gamma-aminobutyric acid (GABA)A and glutamate decarboxylase 65 and restored the glutamate/GABA balance. Nobiletin and CZP administration significantly upregulated phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling.ConclusionNobiletin exerted protective effect against seizures by regulating signaling pathways associated with epileptogenesis and potentiated the effects of CZP.

Beneficial Combination of Lacosamide with Retigabine in Experimental Animals: An Isobolographic Analysis

Background/Aim: To isobolographically determine the types of interactions that occur between retigabine and lacosamide (LCM; two third-generation antiepileptic drugs) with respect to their anticonvulsant activity and acute adverse effects (sedation) in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in adult male Swiss mice. Methods: Type I isobolographic analysis for nonparallel dose-response effects for the combination of retigabine with LCM (at the fixed-ratio of 1:1) in both the MES and chimney test in mice was performed. Brain concentrations of retigabine and LCM were measured by high-pressure liquid chromatography (HPLC) to characterize any pharmacokinetic interactions occurring when combining these drugs. Results: Linear regression analysis revealed that retigabine had its dose-response effect line nonparallel to that of LCM in both the MES and chimney tests. The type I isobolographic analysis illustrated that retigabine combined with LCM (fixed-ratio of 1:1) exerted an additive interaction in the mouse MES model and sub-additivity (antagonism) in the chimney test. With HPLC, retigabine and LCM did not mutually change their total brain concentrations, thereby confirming the pharmacodynamic nature of the interaction. Conclusion: LCM combined with retigabine possesses a beneficial preclinical profile (benefit index ranged from 2.07 to 2.50) and this 2-drug combination is worth recommending as treatment plan to patients with pharmacoresistant epilepsy.

Behavioural Influence of Atorvastatin alone and in Combination with Antiepileptics against Electroconvulsions in Mice

The aim of the present study was to investigate the behavioral influence of atorvastatin alone and in combination with antiepileptics like lacosamide and levetiracetam in the mouse after the experimental convulsions induced by maximal electroshock method. The maximal seizure pattern was induced in mice in alternative days for upto 9 days by giving an alternating current of 45 mA for 0.2 Sec. Atorvastatin (10mg/ kg i.p) were administered intraperitoneally 30 min before the electrical induction of seizures in alone and in combination with lacosamide (10mg/kg i.p) and levetiracetam (10mg/kg i.p). Rota rod, hole board, tail suspension and were used to record behavioral effects periodically. Additionally, the effects of administration of atorvastatin on the adverse effect potential of an lacosamide and levetiracetam were assessed in the chimney test for its motor performance. The results shows that, there is a gradual significant increase of muscle grip strength (p<0.05) and reduction in immobility time (p<0.05) on the 7th day which indicates modulatory effect of atorvastatin on behavior while combining with levetiracetam and lacosamide. In hole board test there was a significant increase in head poking were observed which indicates that the given drug atorvastatin has alleviated the anxiety and depression which confirms its modulatory effects on behavior while combining with levetiracetam and lacosamide. In addition to this atorvastatin in combinations with both antiepileptic drugs had no impact on their adverse effects in the chimney test. Based on the study, the results suggest that the HMG-CoA inhibitor atorvastatin fails to protect the seizures alone and in combination with levetiracetam and shows modulatory effects on behavior while combining with antiepileptics in MES convulsion model.

Additive interactions between retigabine and oxcarbazepine in the chimney test and the model of generalized tonic-clonic seizures in mice

Summary Introduction. Patients with pharmacoresistant epilepsy are usually treated with two or more antiepileptic drugs (AEDs). The search for therapeutically efficacious AED combinations is still a challenging issue for clinicians and epileptologists throughout the world. Aim. To determine the interaction profile for the combination of retigabine (RTG) and oxcarbazepine (OXC) in both, the model of tonic-clonic seizures, the maximal electroshock (MES)-induced seizure model and chimney test (motor performance) in adult male albino Swiss mice. Methods. Isobolographic analysis (type I) was applied to characterize interactions for the combination of RTG with OXC with respect to its anticonvulsant and acute side (neurotoxic) effects, as determined in the MES and chimney tests, respectively. Results. The combination of RTG with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in the MES test in mice. Similarly, the combination of RTG with OXC at the fixed-ratio of 1:1 produced additive interaction with a tendency towards sub-additivity in the chimney test in mice. Measurement of total brain concentrations of both AEDs revealed that RTG did not affect total brain concentrations of OXC and inversely, OXC had no impact on RTG’s total brain concentrations, confirming pharmacodynamic interaction between the drugs. Conclusions. The additive pharmacodynamic interactions in both the MES and chimney tests in mice were observed for the combination of RTG with OXC.

Study of Natural Ventilation Flow in a Room Fitted With a Solar Chimney

The past few decades have seen a considerable change in terms of technological innovation. The recent technological trend is a shift towards the incorporation of natural processes such as hydro, solar and wind in design and implementation. For the purpose of this report, a miniaturised solar chimney test rig was constructed which utilises the principles of natural ventilation. Analysis of similar types of technologies was conducted and various ideas considered in the construction of the test rig. Computational fluid dynamics software was also used in conjunction with the experiment to see the similarities associated with the experiment and software package, taking into account the limitation of various instruments. A comprehensive experimental and theoretical approach was developed and reported.