Study of the acute and repeated dose 28-day oral toxicity in mice treated with PT-31, a molecule with a potential antipsychotic profile

IF 2.8 4区医学 Q2 TOXICOLOGY

Toxicology Mechanisms and Methods Pub Date : 2022-04-11 DOI:10.1080/15376516.2022.2065226

Thalia Emmanoella Sebulsqui Saraiva, Gabriela Zimmermann Prado Rodrigues, Juliana Machado Kayser, E. Dallegrave, Nathália Pulz Maus, Andriele Veiverberg, Gabriel da Costa Berna, Andriéli Carolina Schuster, Maria Gabriela de Freitas, Marina Galdino da Rocha Pitta, I. da Rocha Pitta, G. Gehlen, A. H. Betti

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Abstract

Abstract Schizophrenia is a psychiatric disorder that affects 1% of the world population and is treated with antipsychotics, which may induce important biochemical and hematological alterations. Since it is necessary to verify the safety of new molecules with antipsychotic potential, the present study aimed to evaluate the oral toxicity of PT-31, a putative α2-adrenoreceptor agonist, after acute (2000 mg/kg) and repeated doses (28 days) gavage treatment, in three different doses: minimum effective dose in animal models (10 mg/kg), twice the dose (20 mg/kg), and four times the dose (40 mg/kg), as recommended by the OECD guidelines. Balb/C female adult mice were used, and biochemical, hematological, and histopathological analyses were performed. PT-31 10 and 20 mg/kg did not cause biochemical alterations related to hepatic and renal toxicity, and neither altered glycemic and lipid profiles. The preclinical dose of PT-31 also did not promote mice histopathological changes in the liver, kidney, and brain. In the hematimetric parameters, PT-31 only increased HGB at 20 mg/kg, and MCH and MCHC at 40 mg/kg. However, all the tested doses of PT-31 showed platelet increase, which must be better investigated. Therefore, further studies are needed to investigate the safety of PT-31 as a potential antipsychotic drug.

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PT-31（一种具有潜在抗精神病药物特征的分子）治疗小鼠28天急性和重复剂量口服毒性的研究

摘要精神分裂症是一种影响世界1%人口的精神疾病，使用抗精神病药物治疗，可能会引起重要的生化和血液学改变。由于有必要验证具有抗精神病潜力的新分子的安全性，本研究旨在评估PT-31（一种公认的α2-肾上腺素受体激动剂）在急性（2000 mg/kg）和重复剂量（28 天）灌胃治疗，三种不同剂量：动物模型中的最小有效剂量（10 mg/kg），剂量的两倍（20 mg/kg）和四倍剂量（40 mg/kg）。使用Balb/C雌性成年小鼠，进行生化、血液学和组织病理学分析。PT-31 10和20 mg/kg不会引起与肝肾毒性相关的生化变化，也不会改变血糖和脂质状况。PT-31的临床前剂量也不会促进小鼠肝脏、肾脏和大脑的组织病理学变化。在血液测量参数中，PT-31仅在20时增加HGB mg/kg，以及40时的MCH和MCHC mg/kg。然而，所有测试剂量的PT-31都显示血小板增加，必须对此进行更好的研究。因此，需要进一步研究PT-31作为一种潜在的抗精神病药物的安全性。

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来源期刊

Toxicology Mechanisms and Methods TOXICOLOGY-

自引率

3.10%

发文量

期刊介绍： Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.