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Drug Delivery Letters

Editor-in-Chief

ISSN (Print): 2210-3031
ISSN (Online): 2210-304X

Letter Article

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

Author(s): Cassiana Bigolin, Andriele Veiverberg, Gabriela Zimmermann Prado Rodrigues*, Ana Letícia Hilario Garcia, Juliana Machado Kayser, Fernando Bertoldi, Marcelo Dutra Arbo, Marina Galdino Pitta, Ivan da Rocha Pitta, Günther Gehlen and Andresa Heemann Betti

Volume 13, Issue 4, 2023

Published on: 23 June, 2023

Page: [322 - 328] Pages: 7

DOI: 10.2174/2210303113666230607151339

Price: $65

Abstract

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 atypical profile of the molecule as much as its safety by oral route administration.

Graphical Abstract

[1]
Mizuno, Y.; Suzuki, T.; Nakagawa, A.; Yoshida, K.; Mimura, M.; Fleischhacker, W.W.; Uchida, H. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr. Bull., 2014, 40(6), 1385-1403.
[http://dx.doi.org/10.1093/schbul/sbu030] [PMID: 24636967]
[2]
World Health Organization (Org.). Schizophrenia. 2019. Available From: https://www.who.int/news-room/fact-sheets/detail/schizophrenia
[3]
Orrico-Sánchez, A.; López-Lacort, M.; Muñoz-Quiles, C.; Sanfélix-Gimeno, G.; Díez-Domingo, J. Epidemiology of schizophrenia and its management over 8-years period using real-world data in Spain. BMC Psychiatry, 2020, 20(1), 149.
[http://dx.doi.org/10.1186/s12888-020-02538-8] [PMID: 32248839]
[4]
Laruelle, M. Schizophrenia: From dopaminergic to glutamatergic interventions. Curr. Opin. Pharmacol., 2014, 14, 97-102.
[http://dx.doi.org/10.1016/j.coph.2014.01.001] [PMID: 24524997]
[5]
Stępnicki, P.; Kondej, M.; Kaczor, A.A. Current concepts and treatments of schizophrenia. Molecules, 2018, 23(8), 2087.
[http://dx.doi.org/10.3390/molecules23082087] [PMID: 30127324]
[6]
Brunton, L.L.; Chabner, B.A.; Knollmann, B.C. The Pharmacological Basis of Therapeutics by Goodman & Gilman, 12th ed;McGraw-Hill: Rio de Janeiro,, 2012.
[7]
Meltzer, HY; Gadaleta, E Contrasting Typical and Atypical Antipsychotic Drugs. Focus (Am Psychiatr Publ), 2021 Jan;19(1), 3-13. Epub 2021 Jan 25.
[http://dx.doi.org/10.1176/appi.focus.20200051] [PMID: 34483761] [PMCID: PMC8412155]
[8]
Inder, W.J.; Castle, D. Antipsychotic-induced hyperprolactinaemia. Aust. N. Z. J. Psychiatry, 2011, 45(10), 830-837.
[http://dx.doi.org/10.3109/00048674.2011.589044] [PMID: 21714721]
[9]
Li, P.; Snyder, G.L.; Vanover, K.E. Dopamine targeting drugs for the treatment of schizophrenia: Past, present and future. Curr. Top. Med. Chem., 2016, 16(29), 3385-3403.
[http://dx.doi.org/10.2174/1568026616666160608084834] [PMID: 27291902]
[10]
Divac, N.; Prostran, M.; Jakovcevski, I.; Cerovac, N. Second-generation antipsychotics and extrapyramidal adverse effects. BioMed Res. Int., 2014, 2014(1), 656370.
[PMID: 24995318]
[11]
Briles, J.J.; Rosenberg, D.R.; Brooks, B.A.; Roberts, M.W.; Diwadkar, V.A. Review of the safety of second-generation antipsychotics: Are they really “atypically” safe for youth and adults? Prim. Care Companion CNS Disord., 2012, 14(3), 1-7.
[http://dx.doi.org/10.4088/PCC.11r01298] [PMID: 23106030]
[12]
del Campo, A.; Bustos, C.; Mascayano, C.; Acuña-Castillo, C.; Troncoso, R.; Rojo, L.E. Metabolic syndrome and antipsychotics: The role of mitochondrial fission/fusion imbalance. Front. Endocrinol., 2018, 9(144), 144.
[http://dx.doi.org/10.3389/fendo.2018.00144] [PMID: 29740394]
[13]
Klemp, M.; Tvete, I.F.; Skomedal, T.; Gaasemyr, J.; Natvig, B.; Aursnes, I. A review and Bayesian meta-analysis of clinical efficacy and adverse effects of 4 atypical neuroleptic drugs compared with haloperidol and placebo. J. Clin. Psychopharmacol., 2011, 31(6), 698-704.
[http://dx.doi.org/10.1097/JCP.0b013e31823657d9] [PMID: 22020356]
[14]
de With, S A J.; Pulit, S.L.; Staal, W.G.; Kahn, R.S.; Ophoff, R.A. More than 25 years of genetic studies of clozapine-induced agranulocytosis. Pharmacogenomics J., 2017, 17(4), 304-311.
[http://dx.doi.org/10.1038/tpj.2017.6] [PMID: 28418011]
[15]
Betti, A.H.; Antonio, C.B.; Herzfeldt, V.; Pitta, M.G.R.; da Rocha Pitta, I.; do Rego, J.L.; do Rego, J.C.; Vaudry, D.; Rates, S.M.K. PT-31, a putative α2-adrenoceptor agonist, is effective in schizophrenia cognitive symptoms in mice. Behav. Pharmacol., 2019, 30(7), 574-587.
[http://dx.doi.org/10.1097/FBP.0000000000000494] [PMID: 31206371]
[16]
Bigolin, C.; Sant’Anna Oliveira, T.S.; Cé da Silva, L.; Ayres, T.; Machado Menezes, J.; Da Rocha Pitta, I.; Feiffer Charão, M.; Heemann Betti, A. Evaluation of the potential toxicity of haloperidol, clozapine and a new putative antipsychotic molecule, PT-31, in an alternative toxicity model, C. elegans. Int. J. Innov. Educ. Res., 2020, 8(6), 502-512.
[http://dx.doi.org/10.31686/ijier.vol8.iss6.2446]
[17]
Sommer, S.; Buraczewska, I.; Kruszewski, M. Micronucleus Assay: The state of art, and future directions. Int. J. Mol. Sci., 2020, 21(4), 1534.
[http://dx.doi.org/10.3390/ijms21041534] [PMID: 32102335]
[18]
Szekely, G.; Amores de Sousa, M.C.; Gil, M.; Castelo Ferreira, F.; Heggie, W. Genotoxic impurities in pharmaceutical manufacturing: Sources, regulations and mitigation. Chem. Rev., 2015, 115(16), 8182-8229.
[http://dx.doi.org/10.1021/cr300095f] [PMID: 26252800]
[19]
Neto, M.P.; Gomes, D.C.; Júnior, A.L.; Paz, M.F.; Alencar, M.V.; Islam, M.T.; Ferreira, P.M.; Melo-Cavalcante, A.A. Genotoxic and mutagenic activity of PT-31. Curr. Pharm. Biotechnol., 2016, 17(12), 1043-1048.
[20]
Sudo, R.T.; Calasans-Maia, J.A.; Galdino, S.L.; Lima, M.C.A.; Zapata-Sudo, G.; Hernandes, M.Z.; Pitta, I.R. Interaction of morphine with a new α2-adrenoceptor agonist in mice. J. Pain, 2010, 11(1), 71-78.
[http://dx.doi.org/10.1016/j.jpain.2009.08.001] [PMID: 19853523]
[21]
Kayser, J.M.; Rodrigues, G.Z.P.; Thomazi, C.H.; Hanse, A.W.; Moreira, M.G.; Pitta, M.G.R.; Pitta, I.R.; Ziulkoski, A.L.; Betti, A.H. Cytotoxicity evaluation of haloperidol, clozapine and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells. Braz. J. Pharm. Sci., 2023, 59, e21738.
[http://dx.doi.org/10.1590/s2175-97902023e21738]
[22]
Saraiva, T.E.S.; Rodrigues, G.Z.P.; Kayser, J.M.; Dallegrave, E.; Maus, N.P.; Veiverberg, A.; Berna, G.C.; Schuster, A.C.; de Freitas, M.G.; Pitta, M.G.R.; Pitta, I.R.; Gehlen, G.; Betti, A.H. Study of the acute and repeated dose 28-day oral toxicity in mice treated with PT-31, a molecule with a potential antipsychotic profile. Toxicol. Mech. Methods, 2022, 32(9), 705-715.
[http://dx.doi.org/10.1080/15376516.2022.2065226] [PMID: 35410575]
[23]
Conselho Nacional de Controle de Experimentação Animal.Resolução Normativa nº 37/2018 - Diretriz da Prática de Eutanásiado Conselho Nacional de Controle de Experimentação Animal. 2018. Available From: https://antigo.mctic.gov.br/mctic/export/ sites/institucional/legislacao/Arquivos/Anexo_Res_Norm_37_2018 _CONCEA_Pratica_Eutanasia.pdf
[24]
Galli, C.L.; Cinelli, S.; Ciliutti, P.; Melzi, G.; Marinovich, M. Aloe-emodin, a hydroxyanthracene derivative, is not genotoxic in an in vivo comet test. Regul. Toxicol. Pharmacol., 2021, 124, 104967.
[http://dx.doi.org/10.1016/j.yrtph.2021.104967] [PMID: 34062205]
[25]
Gasparotto, J.; Chaves, P.R.; da Boit Martinello, K.; da Rosa-Siva, H.T.; Bortolin, R.C.; Silva, L.F.O.; Rabelo, T.K.; da Silva, J.; da Silva, F.R.; Nordin, A.P.; Soares, K.; Borges, M.S.; Gelain, D.P.; Moreira, J.C.F. Obese rats are more vulnerable to inflammation, genotoxicity and oxidative stress induced by coal dust inhalation than non-obese rats. Ecotoxicol. Environ. Saf., 2018, 165, 44-51.
[http://dx.doi.org/10.1016/j.ecoenv.2018.08.097] [PMID: 30179764]
[26]
De Sousa, J.A.; De Sousa, J.T.; Boaretto, F.B.M.; Salvi, J.D.O.; Fachini, J.; Da Silva, J.B.; Unfer, J.P.; Allgayer, M.C.; Lemes, M.L.B.; Marroni, N.P.; Ferraz, A.D.B.F.; Picada, J.N. Anti-hyperlipidemic effects of Campomanesia xanthocarpa aqueous extract and its modulation on oxidative stress and genomic instability in Wistar rats. J. Toxicol. Environ. Health A, 2019, 82(18), 1009-1018.
[http://dx.doi.org/10.1080/15287394.2019.1683925] [PMID: 31658881]
[27]
Prá, D.; Franke, S.I.R.; Giulian, R.; Yoneama, M.L.; Dias, J.F.; Erdtmann, B.; Henriques, J.A.P. Genotoxicity and mutagenicity of iron and copper in mice. Biometals, 2008, 21(3), 289-297.
[http://dx.doi.org/10.1007/s10534-007-9118-3] [PMID: 17926008]
[28]
Rojas-Lemus, M.; Altamirano-Lozano, M.; Fortoul, T.I. Sex differences in blood genotoxic and cytotoxic effects as a consequence of vanadium inhalation: Micronucleus assay evaluation. J. Appl. Toxicol., 2014, 34(3), 258-264.
[http://dx.doi.org/10.1002/jat.2873] [PMID: 23620078]
[29]
Karbownik, M.; Lewinski, A.; Reiter, R.J. Anticarcinogenic actions of melatonin which involve antioxidative processes: Comparison with other antioxidants. Int. J. Biochem. Cell Biol., 2001, 33(8), 735-753.
[http://dx.doi.org/10.1016/S1357-2725(01)00059-0] [PMID: 11404179]
[30]
de O Cardoso J.; da Silva, B.F.; Venâncio, T.; da Rocha Pitta, M.G.; da R Pitta, I.; Peccinini, R.G.; Oliveira, R.V. Study of the in vitro metabolic profile of a new α2-adrenergic agonist in rat and human liver microsomes by using liquid chromatography-multiple-stage mass spectrometry and nuclear magnetic resonance. J. Pharm. Biomed. Anal., 2019, 172, 67-77.
[http://dx.doi.org/10.1016/j.jpba.2019.03.067] [PMID: 31029802]
[31]
Picada, J.N.; Dos Santos, B.J.N.; Celso, F.; Monteiro, J.D.; Da Rosa, K.M.; Camacho, L.R.; Vieira, L.R.; Freitas, T.M.; Da Silva, T.G.; Pontes, V.M.; Pereira, P. Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice. Acta Pharmacol. Sin., 2011, 32(10), 1225-1232.
[http://dx.doi.org/10.1038/aps.2011.77] [PMID: 21841809]
[32]
Griffin, S. DNA damage, DNA repair and disease. Curr. Biol., 1996, 6(5), 497-499.
[http://dx.doi.org/10.1016/S0960-9822(02)00525-0] [PMID: 8805281]
[33]
Lalkovicová, M.; Danielisová, V. Neuroprotection and antioxidants. Neural Regen. Res., 2016, 11(6), 865-874.
[http://dx.doi.org/10.4103/1673-5374.184447] [PMID: 27482198]
[34]
Kotanoğlu, M.S.; Kadioğlu, E.; Emerce, E.; Kaymak, Ç.; Özcan, A.; Başar, H. Antioxidant effects of dexmedetomidine against hydrogen peroxide-induced DNA damage in vitro by alkaline Comet assay. Turk. J. Med. Sci., 2020, 50(5), 1393-1398.
[http://dx.doi.org/10.3906/sag-1910-76] [PMID: 31905495]
[35]
Zhang, Y.; Feustel, P.J.; Kimelberg, H.K. Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat. Brain Res., 2006, 1094(1), 200-206.
[http://dx.doi.org/10.1016/j.brainres.2006.03.111] [PMID: 16709402]
[36]
Kutanis, D.; Erturk, E.; Besir, A.; Demirci, Y.; Kayir, S.; Akdogan, A.; Vanizor Kural, B.; Bahat, Z.; Canyilmaz, E.; Kara, H. Dexmedetomidine acts as an oxidative damage prophylactic in rats exposed to ionizing radiation. J. Clin. Anesth., 2016, 34, 577-585.
[http://dx.doi.org/10.1016/j.jclinane.2016.06.031] [PMID: 27687454]
[37]
Bousquet, P.; Hudson, A.; García-Sevilla, J.A.; Li, J.X.; France, C.P. Imidazoline receptor system: The past, the present, and the future. Pharmacol. Rev., 2020, 72(1), 50-79.
[http://dx.doi.org/10.1124/pr.118.016311] [PMID: 31819014]
[38]
Salman, S.; Kumbasar, S.; Gursan, N.; Kumtepe, Y.; Borekci, B.; Polat, B.; Hakan Alp, H.; Talip Sener, M.; Suleyman, H. Investigation of the relationship of some antihypertensive drugs with oxidant/antioxidant parameters and DNA damage on rat uterus tissue. Int. J. Fertil. Steril., 2011, 5(2), 96-103.
[PMID: 24963366]
[39]
Park, S.W.; Phuong, V.T.; Lee, C.H.; Lee, J.G.; Seo, M.K.; Cho, H.Y.; Fang, Z.H.; Lee, B.J.; Kim, Y.H. Effects of antipsychotic drugs on BDNF, GSK-3β, and β-catenin expression in rats subjected to immobilization stress. Neurosci. Res., 2011, 71(4), 335-340.
[http://dx.doi.org/10.1016/j.neures.2011.08.010] [PMID: 21893111]
[40]
Naidoo, U.; Goff, D.C.; Klibanski, A. Hyperprolactinemia and bone mineral density: The potential impact of antipsychotic agents. Psychoneuroendocrinology, 2003, 28(Suppl. 2), 97-108.
[http://dx.doi.org/10.1016/S0306-4530(02)00129-4] [PMID: 12650684]
[41]
Gao, L.; Schäfer, C.; O’Reardon, K.; Gorgus, E.; Schulte-Hubbert, R.; Schrenk, D. The mutagenic potency of onion juice vs. its contents of quercetin and rutin. Food Chem. Toxicol., 2021, 148, 111923.
[http://dx.doi.org/10.1016/j.fct.2020.111923] [PMID: 33316355]
[42]
Valko, M.; Rhodes, C.J.; Moncol, J.; Izakovic, M.; Mazur, M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact., 2006, 160(1), 1-40.
[http://dx.doi.org/10.1016/j.cbi.2005.12.009] [PMID: 16430879]
[43]
Boriollo, M.F.G.; Alves, V.E.; Silva, T.A.; Silva, J.J.; Barros, G.B.S.; Dias, C.T.S.; Höfling, J.F.; Oliveira, N.M.S. Decrease of the DXR-induced genotoxicity and nongenotoxic effects of Theobroma cacao revealed by micronucleus assay. Braz. J. Biol., 2021, 81(2), 268-277.
[http://dx.doi.org/10.1590/1519-6984.223687] [PMID: 32696851]
[44]
Venkatesh, P.; Shantala, B.; Jagetia, G.C.; Rao, K.K.; Baliga, M.S. Modulation of doxorubicin-induced genotoxicity by Aegle marmelos in mouse bone marrow: A micronucleus study. Integr. Cancer Ther., 2007, 6(1), 42-53.
[http://dx.doi.org/10.1177/1534735406298302] [PMID: 17351026]
[45]
Ribeiro, D.A.; Scolastici, C.; Lima, P.L.A.; Marques, M.E.A.; Salvadori, D.M. Genotoxicity of antimicrobial endodontic compounds by single cell gel (comet) assay in Chinese hamster ovary (CHO) cell. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 2005, 99(5), 637-640.

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