Nd anhedonia, each of that are reasonably typical comorbidities of epilepsy.
Nd anhedonia, each of that are somewhat popular comorbidities of epilepsy. An assessment of XEN1101 in acute rodent models of depression and anhedonia was undertaken. The forced swim test (FST) is usually a model of behavioral despair, and is sensitive to several classes of antidepressant drugs. Mice received a single dose of 1 mg/kg or 3 mg/kg XEN1101, 30 mg/kg imipramine, or car. Thirty minutes post-dose, animals had been placed into glass cylinders filled with water. After a period of vigorous activity, mice cease swimming and adopt an immobile posture. More than a 6-min test session, the 1 mg/kg and 3 mg/kg XEN1101 dose groups showed a dose-dependent trend towards improved latency to immobility at the same time as a dose-dependent reduction in time spent immobile (154 49.9 s and 142 42.8 s for 1 and 3 mg/ kg doses, respectively, in comparison with 201 42.9 s for DYRK web automobile (p 0.05)); each indicative of an anti-depressant effect. The progressive ratio test (PRT) is usually a model of anhedonia. The effect of XEN1101 on the motivation of educated rats to respond having a lever press for any meals reward was assessed. The rats followed a progressive schedule of reinforcement in which the amount of lever presses needed to get a meals reward enhanced for successive reinforcers. The break point was defined as the point at which a rat failed to earn a food pellet in 20 min. The amount of meals pellets earned was the major measure of efficacy, with increases indicating improvements in anhedonia. In a crossover design, rats received a single dose of 1, 3, or eight mg/kg XEN1101, 0.6 mg/kg amphetamine (as a good control), or car. XEN1101 drastically enhanced the number of food pellets earned in the break point for both the 3 mg/kg (n = 12.five 0.4) and 8 mg/kg doses (n = 12.8 0.5), respectively, compared to n = 11.5 0.five for automobile (p 0.05 and p 0.01, respectively). The outcomes from these two research help a prospective benefit of XEN1101 in mood disorders.ASENT2021 Annual Meeting AbstractsAbstract 21 Anticonvulsant Effects from the Differentiated Kv7 Channel Potentiator XEN1101 in Combination with Frequently Made use of Anti-seizure Drugs J.P. Johnson, Jr., Girish Bankar, Celine Dube, Parisa Tari, Karen Nelkenbrecher, Matthew Waldbrook, Nina Weishaupt, Gregory Beatch, Jeff Bechard, EAAT2 Compound Rostam Namdari, Robin Sherrington, Alison Cutts, Charles Cohen, James Empfield; Xenon Pharmaceuticals, Inc. XEN1101 is often a good allosteric modulator of Kv7 channels being developed for the therapy of epilepsy. Combination of anti-seizure drugs (ASDs) is common in clinical practice. Hence we examined the possible for combination therapy with XEN1101 as well as other ASDs. The efficacy of XEN1101 was evaluated in mixture with valproic acid, phenytoin, or levetiracetam inside the direct current maximum electroshock seizure assay (DC-MES). The combined efficacy of XEN1101 and levetiracetam was also evaluated within the 6-Hz psychomotor seizure assay (six Hz). We tested the efficacy of XEN1101 in combination with phenytoin within the DC-MES assay. A weakly efficacious dose of phenytoin (2 mg/kg protected 25 of mice) was combined with XEN1101 at 0.75, 1, 1.five, and 2.five mg/kg in the DC-MES assay. XEN1101 was efficient, with a total plasma EC50 of 0.154 when dosed alone and 0.04 when dosed in combination with phenytoin, a 3.85-fold boost in apparent potency. We next tested XEN1101 within the DC-MES assay in mixture with valproic acid. A weakly efficacious dose of XEN1101 (1 mg/kg protected 30 of mice) was combined w.
