Dataset Information

Selective H3 Antagonist (ABT-239) Differentially Modifies Cognitive Function Under the Impact of Restraint Stress.

ABSTRACT: Background: A considerable number of competitive antagonists/inverse agonists of histamine H3 receptor (H3R) have progressed to clinical assessment, with pitolisant approved for the treatment of narcolepsy. H3R, highly expressed in the CNS, is regarded as a relevant target in CNS disorders. At the same time, new compounds including ABT-239 H3R antagonist (ABT; benzonitrile, 4-[2-[2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl]-5-benzofuranyl]-) are continually being tested. The study aimed to test ABT-239 as a prophylactic agent in stress-induced memory impairments. Methods: Stressed and non-stressed rats were pre-treated with ABT-239 and subsequently subjected to several behavioral tests aimed at assessing the animals' working and spatial reference memory [Morris water maze (MWM), Barnes maze (BM)], assessing the locomotor function and anxiety-like behavior [Open field (OF), elevated "plus" maze-EPM]. Results: Chronically stressed rats displayed a significant decline in spatial (working and reference) memory. In the MWM test, we observed an improvement in spatial reference memory in stressed animals and a positive after ABT-239 pre-treatment. In the BM test, the effect of ABT-239 administration on spatial memory changed in successive attempts, from negative initially to favorable in subsequent attempts, and negative in the last trial of the test in the control group of rats. However, a beneficial effect is noted in the group of stressed animals, which remained throughout the entire testing period. Conclusions: Presented findings demonstrate that ABT-239 shows the potential to abolish or prevent restraint stress-induced spatial memory impairments and cognitive deficits. However, in conditions of appetitive modulation, it could increase damage to memory (unstressed animals).

SUBMITTER: Trofimiuk E

PROVIDER: S-EPMC7884464 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Selective H3 Antagonist (ABT-239) Differentially Modifies Cognitive Function Under the Impact of Restraint Stress.

Trofimiuk Emil E Wielgat Przemysław P Car Halina H

Frontiers in systems neuroscience 20210202

<b>Background</b>: A considerable number of competitive antagonists/inverse agonists of histamine H3 receptor (H3R) have progressed to clinical assessment, with pitolisant approved for the treatment of narcolepsy. H3R, highly expressed in the CNS, is regarded as a relevant target in CNS disorders. At the same time, new compounds including ABT-239 H3R antagonist (ABT; benzonitrile, 4-[2-[2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl]-5-benzofuranyl]-) are continually being tested. The study aimed to test ...[more]

PMID: 33603652

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Project description:BackgroundH3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated.MethodsPatients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence.FindingsAmong the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms.InterpretationThe clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

Dataset Information

Selective H3 Antagonist (ABT-239) Differentially Modifies Cognitive Function Under the Impact of Restraint Stress.

Publications

Selective H3 Antagonist (ABT-239) Differentially Modifies Cognitive Function Under the Impact of Restraint Stress.

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