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

Saraiva, Thalia Emmanoella Sebulsqui; Rodrigues, Gabriela Zimmermann Prado; Kayser, Juliana Machado; Dallegrave, Eliane; Maus, Nathália Pulz; Veiverberg, Andriele; Berna, Gabriel da Costa; Schuster, Andriéli Carolina; Freitas, Maria Gabriela de; Pitta, Marina Galdino da Rocha; Pitta, Ivan da Rocha; Gehlen, Günther; Betti, Andresa Heemann

doi:10.1080/15376516.2022.2065226

Cited by 2 publications

(3 citation statements)

References 72 publications

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“…Being usually accompanied by less food and water intake, body weight change is stimulated by proinflammatory cytokines that promote protein degradation and loss of skeletal musculature through influence on energy homeostasis in hypothalamic regions (Tizard, 2008; Gomes et al ., 2018). In a previous study from our research group (Saraiva et al ., 2022), the repeated-dose 28-day treatment with PT-31 (10, 20, and 40 mg/kg) did not significantly change the animals’ body weight. In the present study, PT-31 per se also presented less body weight change when compared to the vehicle group, and this is probably because of an antilipolytic action after α₂-adrenoceptor activation (Carpené et al , 1990).…”

Section: Discussionmentioning

confidence: 89%

“…After 5 h from lipopolysaccharide administration, animals received saline plus 1% Tween 80 (naïve and vehicle groups), PT-31 ( per se , PT3, PT10, and PT30 groups), or fluoxetine (positive control group) by oral gavage (10 mg/kg of body weight). PT-31 doses were selected based on previous studies with this molecule (Sudo et al ., 2017; Betti et al ., 2019; Saraiva et al ., 2022). Six hours after lipopolysaccharide administration, all animals were subjected to the open field test (OFT).…”

Section: Methodsmentioning

confidence: 99%

“…In toxicological sstudies, the molecule did not affect survival, body length, or area of the alternative toxicity model Caenorhabditis elegans (Bigolin et al ., 2020). Last but not least, our research group also evaluated PT-31 in a repeated-dose 28-day oral toxicity study, in which the preclinical dose of PT-31 (10 mg/kg) did not cause biochemical alterations regarding hepatic and renal toxicity, and neither promoted histopathological changes in liver, kidney, nor brain of mice (Saraiva et al ., 2022). Although previous studies suggest a putative central anti-inflammatory effect of PT-31 as other hydantoins (Nascimento et al ., 2018a), the role of this molecule against inflammation-induced depression has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Antidepressant effect of PT-31, an α₂-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in mice

Machado Kayser,

Petry,

Alijar Souza

et al. 2024

Behavioural Pharmacology

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Increasing evidence indicates that neuroinflammation, oxidative stress, and neurotrophic factors play a key role in the pathophysiology of major depressive disorder (MDD). In addition, the attenuation of inflammatory response has been considered a putative mechanism for MDD treatment. PT-31 is an imidazolidine derivative and a putative α₂-adrenoceptor agonist that has previously demonstrated antinociceptive activity. The present study aimed to investigate the effect of PT-31 on depressive-like behavior and lipopolysaccharide-induced neurochemical changes. To this end, mice received intraperitoneally saline or lipopolysaccharide (600 µg/kg), and 5 h postinjection animals were orally treated with saline, PT-31 (3, 10, and 30 mg/kg), or fluoxetine (30 mg/kg). Mice were subjected to the open field test (OFT) 6 and 24 h after lipopolysaccharide administration and to the tail suspension test (TST) 24 h postlipopolysaccharide. Subsequently, animals were euthanized, and brains were dissected for neurochemical analyses. The administration of lipopolysaccharide-induced sickness- and depressive-like behaviors, besides promoting an increase in myeloperoxidase activity and a reduction in brain-derived neurotrophic factor (BDNF) levels. Noteworthy, PT-31 3 mg/kg attenuated lipopolysaccharide-induced decreased locomotor activity 6 h after lipopolysaccharide in the OFT. All tested doses of PT-31 significantly reduced the immobility time of animals in the TST and attenuated lipopolysaccharide-induced increased myeloperoxidase activity in the cortex of mice. Our results demonstrate that PT-31 ameliorates behavioral changes promoted by lipopolysaccharide in OFT and TST, which is possibly mediated by attenuation of the inflammatory response.

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Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antidepressant effect of PT-31, an α₂-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in mice

Machado Kayser,

Petry,

Alijar Souza

et al. 2024

Behavioural Pharmacology

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Genotoxic and Mutagenic Assessment of PT-31, a Molecule with Antipsychotic Potential

Bigolin,

Veiverberg,

Prado Rodrigues

et al. 2023

DDL

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The PT-31 molecule, a potential antipsychotic, has demonstrated promising results when orally administrated to in vivo models. A recent study suggested the genotoxic and mutagenic potential of PT-31 after acute treatment by intraperitoneal route. This study aimed to evaluate PT-31 potential of inducing genotoxic or mutagenic damage after acute oral administration. For that, adult males and females Balb/C mice were treated acutely by oral administration with vehicle or PT-31 in three different doses (10, 20, and 40 mg kg-1). After 24 hours from PT-31 administration, animals were euthanized for performing the comet and micronucleus assays. None of the tested groups of PT-31 presented a significant increase in damage index and MN frequency. However, they presented the following tendency on damage index: females presented a tendency at 40 mg kg-1 and males at 20 mg kg-1. Regarding the MN assay, male mice at the highest dose of 40 mg kg-1 presented a tendency of increased MN frequency. Also, there was a significant increase in PCE/NCE ratio in male mice. Results suggest that the male mice group presented higher susceptibility to damage. The tendency of increased damage to DNA and MN frequency suggests that the molecule PT-31 may induce reparable damage to DNA, and these DNA strand repairs may have originated from the MN. However, significant genotoxic and mutagenic effects were not observed. This study reinforces the atypicality of the molecule as much as its safety by oral route administration.

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

Cited by 2 publications

References 72 publications

Antidepressant effect of PT-31, an α₂-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in mice

Antidepressant effect of PT-31, an α₂-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in mice

Genotoxic and Mutagenic Assessment of PT-31, a Molecule with Antipsychotic Potential

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