Effect of Co-Treatment of Olanzapine with SEP-363856 in Mice Models of Schizophrenia

Liang, Lingzhi; Ren, Xia; Xu, Jianguo; Ma, Yurong; Xue, Yunlin; Zhuang, Tao; Zhang, Guisen

doi:10.3390/molecules27082550

Cited by 9 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Escape latency, defined as the time needed by the animal to find the platform, was the basic parameter measured each day of training and was regarded as a measurement of spatial learning, which was impaired by scopolamine and MK-801. The impact of both compounds was comparable to other studies [ 16 , 17 , 20 , 21 , 22 ]. On the test day, the escape platform was removed, and the mice were allowed to search for it for a fixed time (60 s).…”

Section: Discussionsupporting

confidence: 89%

A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

2023

View full text Add to dashboard Cite

Learning and memory deficits accompany numerous brain dysfunctions, including schizophrenia and Alzheimer’s disease (AD), and many studies point to the role of nitric oxide (NO) in these processes. The present investigations constitute the follow-up of our previous research, in which we investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) to prevent short-term memory deficits in novel object recognition and T-maze. Here, the ability of the compounds to prevent the induction of long-term memory deficits by MK-801 or scopolamine administration was investigated. The Morris Water Maze test, a reliable and valid test of spatial learning and memory, was used, in which escape latency in the acquisition phase and nine different parameters in the retention phase were measured. A fast NO releaser (spermine NONOate), a slow NO releaser (DETA NONOate), and a nNOS inhibitor, N(ω)-propyl-L-arginine (NPLA), were used. The compounds were administered i.p. at a dose range of 0.05–0.5 mg/kg. All compounds prevented learning deficits in the acquisition phase and reversed reference memory deficits in the retention phase of the scopolamine-treated mice. Spermine NONOate was the least effective. In contrast, the drugs poorly antagonised MK-801-induced deficits, and only the administration of DETA NONOate induced some improvements in the retention trial.

show abstract

Section: Discussionsupporting

confidence: 89%

A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

2023

View full text Add to dashboard Cite

show abstract

“…Similar data were obtained when the effect of ulotaront was evaluated in the dopamine agonist apomorphine-induced climbing test in mice [62]. At the same time, treatment with ulotaront potentiated effects of the antipsychotic drug olanzapine in this test as well as in the NMDA antagonist MK-801-induced hyperactivity test in mice [62].…”

Section: Antipsychotic Action: Positive Symptomssupporting

confidence: 77%

“…Ulotaront at 10 mg/kg also ameliorated cognitive impairments caused by sub-chronic treatment with PCP in the novel object recognition test in rats [61]. Furthermore, ulotaront slightly mitigated MK-801-induced deficits in the Morris water maze test and potentiated the ameliorative effect of olanzapine in this cognitive assay [62]. Deficits in sensorimotor gating are present in patients suffering from schizophrenia, and these deficits can be modeled in rodents.…”

Section: Antipsychotic Action: Negative Symptoms and Cognitive Deficitsmentioning

confidence: 86%

Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders

et al. 2023

View full text Add to dashboard Cite

All antipsychotics currently used in clinic block D2 dopamine receptors. Trace amine-associated receptor 1 is emerging as a new therapeutic target for schizophrenia and several other neuropsychiatric disorders. SEP-363856 (International Nonproprietary Name: Ulotaront) is an investigational antipsychotic drug with a novel mechanism of action that does not involve antagonism of dopamine D2 receptors. Ulotaront is an agonist of trace amine-associated receptor 1 and serotonin 5-HT1A receptors, but can modulate dopamine neurotransmission indirectly. In 2019, the United States Food and Drug Administration granted Breakthrough Therapy Designation for ulotaront for the treatment of schizophrenia. Phase 2 clinical studies indicated that ulotaront can reduce both positive and negative symptoms of schizophrenia without causing the extrapyramidal or metabolic side effects that are inherent to most currently used antipsychotics. At present, it is in phase 3 clinical development for the treatment of schizophrenia and is expected to be introduced into clinical practice in 2023–2024. Clinical studies evaluating the potential efficacy of ulotaront in Parkinson’s disease psychosis, generalized anxiety disorder, and major depressive disorder have also been started. The aim of this scoping review is to summarize all currently available preclinical and clinical evidence on the utility of ulotaront in the treatment of schizophrenia. Here, we show the main characteristics and distinctive features of this drug. Perspectives and limitations on the potential use of ulotaront in the pharmacotherapy of several other neuropsychiatric disorders are also discussed.

show abstract

“…Weight‐lowering effects, accompanied by reductions in food intake, were reported for TAAR1 agonists in rodent models of diet‐induced obesity and iatrogenic (e.g. olanzapine‐induced) weight gain 22,23,26,27 . In addition, improved glucose tolerance and insulin sensitivity, as well as reduced plasma and liver triglyceride levels, were seen in diet‐induced obesity and/or db/db mice (a genetic model of type 2 diabetes) 23,26 .…”

Section: Introductionmentioning

confidence: 90%

“…olanzapine-induced) weight gain. 22,23,26,27 In addition, improved glucose tolerance and insulin sensitivity, as well as reduced plasma and liver triglyceride levels, were seen in diet-induced obesity and/or db/db mice (a genetic model of type 2 diabetes). 23,26 TAAR1 agonists also delay gastric emptying (GE) in rodents, 23,26 a mechanism implicated in the weight-lowering effects of glucagon-like peptide-1 receptor (GLP-1R) agonists.…”

Section: Introductionmentioning

confidence: 99%

TAAR1 agonist ulotaront delays gastric emptying of solids in patients with schizophrenia and concurrent metabolic syndrome with prediabetes

Milanović,

Dedic,

Lew

et al. 2024

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

BackgroundMetabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine‐associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non‐clinical studies have also shown weight‐lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes.MethodsPatients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open‐label, crossover, two‐sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7‐6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post‐dose, participants ingested a 99mTc‐sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half‐time (T1/2) and percentage gastric retention at 1, 2 and 4 h.ResultsThirty‐one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post‐meal.ConclusionUlotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.

show abstract

Effect of Co-Treatment of Olanzapine with SEP-363856 in Mice Models of Schizophrenia

Cited by 9 publications

References 50 publications

A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders

TAAR1 agonist ulotaront delays gastric emptying of solids in patients with schizophrenia and concurrent metabolic syndrome with prediabetes

Contact Info

Product

Resources

About