Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice.

IF 1.2 4区 医学 Q4 PHARMACOLOGY & PHARMACY
International Journal of Toxicology Pub Date : 2023-12-01 Epub Date: 2023-08-09 DOI:10.1177/10915818231193634
Forrest Enemark, Zachary M Novakovic, Patricia Grasso
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引用次数: 0

Abstract

Although the regulatory influence of leptin on energy balance, glycemic control, immunity, reproduction, and cognition is well established, its clinical application to common obesity and its co-morbidities has been limited by impaired transport across the blood-brain barrier, and tendencies to induce adverse side effects. To circumvent these drawbacks, MA-[D-Leu-4]-OB3, a leptin-related synthetic peptide that mimics the metabolic and neurotrophic effects of leptin in mouse models of genetic and non-genetic obesity, diabetes, and cognitive dysfunction, has been developed. This report presents the results of our initial efforts to assess the safety of orally delivered MA-[D-Leu-4]-OB3. Two pre-clinical studies were done in male and female C57BL/6 mice: a short-term study with a high dose of MA-[D-Leu-4]-OB3 (50 mg/kg/100 μL/day) and a dose-response study with 3 increasing concentrations of MA-[D-Leu-4]-OB3 (16.6, 50, and 150 mg/kg/100 μL/day). Body weight, food and water intake, glucose tolerance, and episodic memory were evaluated. Once-daily cage-side clinical observations were conducted to detect any physical or behavioral indicators of toxicity. Our results indicate that all metabolic and neurologic endpoints tested were either unaffected or improved by MA-[D-Leu-4]-OB3, and no clinical indicators of toxicity were evident. Together with our previously reported efficacy data, these results provide additional evidence supporting further development of this novel synthetic peptide leptin mimetic as a first-in-class peptide drug candidate for the treatment of a number of metabolic and/or cognitive dysfunctions in humans.

MA-[D-Leu-4]- ob3对C57BL/6小鼠的两项临床前毒性研究
尽管瘦素对能量平衡、血糖控制、免疫、生殖和认知的调节作用已经得到了很好的证实,但其在常见肥胖及其合并症中的临床应用受到了血脑屏障运输受损和诱发不良副作用的趋势的限制。为了克服这些缺点,已经开发了一种与瘦素相关的合成肽MA-[D-Leu-4]-OB3,它模拟了瘦素在遗传性和非遗传性肥胖、糖尿病和认知功能障碍小鼠模型中的代谢和神经营养作用。本报告介绍了我们初步评估口服MA-[D-Leu-4]-OB3安全性的结果。在雄性和雌性C57BL/6小鼠中进行了两项临床前研究:一项是高剂量MA-[D-Leu-4]-OB3(50 mg/kg/100μL/天)的短期研究,另一项是增加3个浓度的MA-[DLeu-4]-OB3(16.6、50和150 mg/kg/100µL/天。评估了体重、食物和水的摄入量、葡萄糖耐量和情景记忆。每天进行一次笼侧临床观察,以检测任何毒性的物理或行为指标。我们的结果表明,所有测试的代谢和神经终点都没有受到MA-[D-Leu-4]-OB3的影响或得到改善,并且没有明显的毒性临床指标。结合我们之前报道的疗效数据,这些结果提供了额外的证据,支持这种新型合成肽瘦素模拟物作为第一类候选肽药物的进一步开发,用于治疗人类的许多代谢和/或认知功能障碍。
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来源期刊
CiteScore
3.40
自引率
4.50%
发文量
53
审稿时长
4.5 months
期刊介绍: The International Journal of Toxicology publishes timely, peer-reviewed papers on current topics important to toxicologists. Six bi-monthly issues cover a wide range of topics, including contemporary issues in toxicology, safety assessments, novel approaches to toxicological testing, mechanisms of toxicity, biomarkers, and risk assessment. The Journal also publishes invited reviews on contemporary topics, and features articles based on symposia. In addition, supplemental issues are routinely published on various special topics, including three supplements devoted to contributions from the Cosmetic Review Expert Panel.
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