Nd anhedonia, both of that are comparatively popular comorbidities of TRPV medchemexpress epilepsy.
Nd anhedonia, each of which are reasonably common 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 many 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 have been placed into glass cylinders filled with water. After a period of vigorous activity, mice cease swimming and adopt an immobile posture. Over a 6-min test session, the 1 mg/kg and three mg/kg XEN1101 dose groups showed a dose-dependent trend towards elevated latency to immobility as well as a dose-dependent reduction in time spent immobile (154 49.9 s and 142 42.8 s for 1 and three mg/ kg doses, respectively, compared to 201 42.9 s for vehicle (p 0.05)); both indicative of an anti-depressant effect. The progressive ratio test (PRT) is often a model of anhedonia. The impact of XEN1101 around the motivation of educated rats to respond using a lever press to get a 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 because the point at which a rat failed to earn a meals pellet in 20 min. The amount of food pellets earned was the major measure of efficacy, with increases indicating improvements in anhedonia. Inside a crossover design, rats received a single dose of 1, three, or eight mg/kg XEN1101, 0.6 mg/kg amphetamine (as a constructive handle), or vehicle. XEN1101 significantly improved the amount of food pellets earned at the break point for each the 3 mg/kg (n = 12.5 0.four) and 8 mg/kg doses (n = 12.eight 0.5), respectively, in comparison with n = 11.5 0.five for automobile (p 0.05 and p 0.01, respectively). The outcomes from these two studies help a potential advantage of XEN1101 in mood disorders.ASENT2021 Annual Meeting AbstractsAbstract 21 Anticonvulsant Effects from the Differentiated Kv7 Channel Potentiator XEN1101 in Combination with Typically Applied Anti-seizure Drugs J.P. Johnson, Jr., Girish Bankar, Celine Dube, Parisa Tari, Karen Nelkenbrecher, Matthew Waldbrook, Nina Weishaupt, Gregory Beatch, Jeff Bechard, Rostam Namdari, Robin Sherrington, Alison Cutts, Charles Cohen, James Empfield; Xenon Pharmaceuticals, Inc. XEN1101 is a positive allosteric modulator of Kv7 channels being developed for the remedy of epilepsy. Mixture of anti-seizure drugs (ASDs) is frequent in clinical practice. Hence we examined the prospective for combination therapy with XEN1101 as well as other ASDs. The efficacy of XEN1101 was evaluated in mixture with valproic acid, phenytoin, or levetiracetam within the direct current maximum electroshock seizure assay (DC-MES). The combined efficacy of XEN1101 and levetiracetam was also evaluated inside the 6-Hz psychomotor seizure assay (six Hz). We Gap Junction Protein Storage & Stability tested the efficacy of XEN1101 in mixture with phenytoin in the DC-MES assay. A weakly efficacious dose of phenytoin (two mg/kg protected 25 of mice) was combined with XEN1101 at 0.75, 1, 1.five, and 2.5 mg/kg inside the DC-MES assay. XEN1101 was helpful, with a total plasma EC50 of 0.154 when dosed alone and 0.04 when dosed in mixture with phenytoin, a 3.85-fold raise in apparent potency. We next tested XEN1101 inside the DC-MES assay in combination with valproic acid. A weakly efficacious dose of XEN1101 (1 mg/kg protected 30 of mice) was combined w.