Skip to main content

Advertisement

SpringerLink
Log in

Clozapine linked to nanocapsules minimizes tissue and oxidative damage to biomolecules lipids, proteins and DNA in brain of rats Wistar

  • Research Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Clozapine, atypical antipsychotic, can change oxidative stress parameters. It is known that reactive species, in excess, can have a crucial role in the etiology of diseases, as well as, can potentiating adverse effects induce by drugs. The nanocapsules have attracted attention as carriers of several drugs, with consequent reduction of adverse effects. This study aimed to evaluate histopathology and oxidative damage of biomolecules lipids, proteins and DNA in the brain of Wistar rats after treatment with nanocapsules containing clozapine. The study consisted of eight groups of male Wistar rats (n = 6): saline (SAL), free clozapine (CZP) (25 mg/Kg i.p.), blank uncoated nanocapsules (BNC), clozapine-loaded uncoated nanocapsules (CNC) (25 mg/Kg i.p.), blank chitosan-coated nanocapsules (BCSN), clozapine-loaded chitosan-coated nanocapsules (CCSN) (25 mg/Kg i.p.), blank polyethyleneglycol-coated nanocapsules (BPEGN), clozapine-loaded polyethyleneglycol-coated nanocapsules (CPEGN) (25 mg/Kg i.p.). The animals received the formulation once a day for seven consecutive days and euthanized in the eighth day. After euthanasia, the brain was collected and homogenate was processed for further analysis. The histopathology showed less brain tissue damage in nanocapsules-treated groups. The lipid peroxidation and carbonylation of proteins showed a significant increase (p < 0.05) induced by CZP. CNC and CPEGN groups obtained a reduction membrane of lipids damage and nanocapsules-treated groups showed significant improvement protein damage. CZP was able to induce genetic oxidative damage, while the nanocapsules causing less damage to DNA. The findings show that different coatings can act protecting target tissues decreasing oxidative damage, suggesting that the drug when linked to different nanocapsules is able to mitigate the harmful effects of clozapine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdel-Wahab BA, Abdalla ME, El-khawanki MM (2014a) Does clozapine induce myocarditis, myocardial oxidative stress and DNA damage in rats? Eur J Pharmacol 592:123–127

    Google Scholar 

  • Abdel-Wahab BA et al (2014b) Protective effect of captopril against clozapine-induced myocarditis in rats: role of oxidative stress, proinflammatory cytokines and DNA damage. Chem Biol Interact 216:43–52

    Article  CAS  PubMed  Google Scholar 

  • Agostinho FR et al (2007) Effects of chronic haloperidol and/or clozapine on oxidative stress parameters in rat brain. Neurochem Res 32:1343–1350

    Article  CAS  PubMed  Google Scholar 

  • Atkin K et al (1996) Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry 169:483–488

    Article  CAS  PubMed  Google Scholar 

  • Beck RCR et al (2005) Nanostructure-coated diclofenac-loaded microparticles: preparation, morphological characterization, in vitro release and in vivo gastrointestinal tolerance. J Braz Chem Soc 16:1233–1240

    Article  CAS  Google Scholar 

  • Beck RCR et al (2006) Nanoparticle-coated organic-inorganic microparticles: experimental design and gastrointestinal tolerance evaluation. Quim Nova 29:990–996

    Article  CAS  Google Scholar 

  • Benvegnú DM, Barcelos RCS, Boufleur N et al (2011) Haloperidol-loaded polysorbate-coated polymeric nanocapsules increase its efficacy in the antipsychotic treatment in rats. Eur J Pharm Biopharm 77:332–336

    Article  PubMed  Google Scholar 

  • Benvegnú DM et al (2012) Haloperidol-loaded polysorbate-coated polymeric nanocapsules decrease its adverse motor side effects and oxidative stress markers in rats. Neurochem Int 61:623–631

    Article  PubMed  Google Scholar 

  • Bergemann et al (2007) High clozapine concentrations in leukocytes in a patient who developed leukocytopenia. Prog Neuro-Psychopharmacol Biol Psychiatry 31:1068–1071

    Article  CAS  Google Scholar 

  • Bernardi A et al (2009) Indomethacin-loaded nanocápsulas treatment reduces in vivo glioblastoma growth in a rat glioma model. Cancer Lett 281:53–63

    Article  CAS  PubMed  Google Scholar 

  • Bernardi A et al (2010) Protective effects of indomethacin-loaded nanocapsules against oxygen-glucose deprivation in organotypic hippocampal slice cultures: involvement of neuroinflammation. Neurochem Int 57:629–636

    Article  CAS  PubMed  Google Scholar 

  • Bieniek DD et al (2011) Validação de metodologia analítica por cromatografia líquida de alta eficiência para doseamento de clozapina em nanopartículas poliméricas. Perspectiva 35(129):17–26

    Google Scholar 

  • Brasil (2008) Law n° 11.794, 08 October 2008. http://www.planalto.gov.br/ccivil_03/_Ato2007-2010/2008/Lei/L11794.htm. Accessed 21 May 2014

  • Brasil (2013) Ministery of Science, Tecnology e Inovation National Council for the Control of Animal Experimentation – CONCEA

  • Buur-Rasmussen B, Brosen K (1999) Cytochrome P450 and therapeutic drug monitoring with respect to clozapine. Eur Neuropsychopharmacol 9:453–459

    Article  CAS  PubMed  Google Scholar 

  • Canadian Council Animal Care (1993) Guide to the Care and Use of experimental Animals. http://www.ccac.ca/Documents/Standards/Guidelines/Experimental_Animals_Vol1.pdf. Accessed 10 May de 2014

  • Correll CU, Gallego JA (2012) Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. Psychiatr Clin N Am 35(3):661–681

    Article  Google Scholar 

  • Dal-Pizzol F et al (2000) Lipid peroxidation in hippocampus early and late after status epilepticus induced by pilocarpine or kainic acidin Wistar rats. Neurosci Lett 291:179–182

    Article  CAS  PubMed  Google Scholar 

  • Dal-Pizzol F et al (2001) Retinol supplementation induces oxidative stress and modulates antioxidant enzyme activities in rat Sertoli cells. Free Radic Res 34:395–404

    Article  CAS  PubMed  Google Scholar 

  • Elkis H & Meltzer HY (2007) Esquizofrenia refratária. Revista Brasileira de Psiquiatria 29:II:S41-S47

  • Figueredo VM (2011) Chemical cardiomyopathies: the negative effects of medications and nonprescribed drugs on the heart. Am J Med 124:480–488

    Article  CAS  PubMed  Google Scholar 

  • Flanagan R, Dunk L (2008) Haematological toxicity of drugs used in psychiatry. Hum Psychopharmacol Clin Exp 23:27–41

    Article  CAS  Google Scholar 

  • Fontana MC et al (2011) Improved efficacy in the treatment of contact dermatitis in rats by a dermatological nanomedicine containing clobetasol propionate. Eur J Pharm Biopharm 79:241–249

    Article  CAS  PubMed  Google Scholar 

  • Gaszner P, Makkos Z, Kosza P (2002) Agranulocytosis during clozapine therapy. Prog Neuro-Psychopharmacol Biol Psychiatry 26:603–607

    Article  CAS  Google Scholar 

  • Haas SJ et al (2007) Clozapineassociated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993–2003. Drug Saf 30(1):47–57

    Article  CAS  PubMed  Google Scholar 

  • Haixiong G et al (2002) Preparation, characterization, and drug release behaviors of drug nimodipine-loaded poly (e-caprolactone)–poly (ethylene oxide)–poly ecaprolactone) amphiphilic triblock copolymer micelles. J Pharm Sci 91:1463–1473

    Article  Google Scholar 

  • Hogan K, Ahmed O, Markos F (2007) N-desmethylclozapine an M1 receptor agonist enhances nitric oxide’s cardiac vagal facilitation in the isolated innervated rat right atrium. Auton Neurosci 137(1–2):51–55

    Article  CAS  PubMed  Google Scholar 

  • Husain Z et al (2006) Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine. Toxicol Appl Pharmacol 214:326–334

    Article  CAS  PubMed  Google Scholar 

  • Jann MW (1991) Clozapine. Pharmacotherapy 11(3):179–195

    CAS  PubMed  Google Scholar 

  • Jann MW et al (1993) Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet 24(2):161–176

    Article  CAS  PubMed  Google Scholar 

  • Landsiedel R et al (2009) Genotoxicity investigations on nanomaterials: methods, preparations and characterization of test material, potential artifacts and limitations – many questions, some answers. Mutat Res 681:241–258

  • Levine RL et al (1990) Damage to proteins and lipids tissues under oxidative stress. Meth Enzymol 186:464–478

  • Lous JAEDVT et al (2003) CYP1A2 activity is an important determinant of clozapina dosage in schizophrenic patients. Eur J Pharm Sci 20:451–457

    Article  Google Scholar 

  • Manu P et al (2012) When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res 134(2–3):180–186

    Article  PubMed Central  PubMed  Google Scholar 

  • Mcilwain ME, Harrison J, Wheeler AJ et al (2011) Pharmacotherapy for treatment-resistant Schizophrenia. Neuropsychiatr Dis Treat 7:135–149

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ohkawa H, Ohishi H, Yagi K (1979) Assay for lipid peroxide in animal tissues by thiobarbituric acid reaction. Ann Biochem 95:351–358

    Article  CAS  Google Scholar 

  • Pereira A, Dean B (2006) Clozapine bioactivation induces dose dependent, drug-specific toxicity of human bone marrow stromal cells: a potential in vitro system for the study of agranulocytosis. Biochem Pharmacol 72:783–793

    Article  CAS  PubMed  Google Scholar 

  • Pirmohamed M, Park K (1997) Mechanism of clozapine-induced agranulocytosis. Current status of research and implications for drug development. CNS Drugs 7:139–158

    Article  CAS  PubMed  Google Scholar 

  • Polydoro M, Schröder N, Lima MNM et al (2004) Haloperidol- and clozapine-induced oxidative stress in the rat brain. Pharmacol Biochem Behav 78:751–756

    Article  CAS  PubMed  Google Scholar 

  • Reinke A, Martins MR, Lima MS et al (2004) Haloperidol and clozapine, but not olanzapine, induces oxidative stress in rat brain. Neurosci Lett 372:157–160

    Article  CAS  PubMed  Google Scholar 

  • Salata O (2004) Applications of nanoparticles in biology and medicine. J Nanobiotechnology 2:3–9

    Article  PubMed Central  PubMed  Google Scholar 

  • Schäfer I, Lambert M, Naber D (2004) Atypical antipsychotics in therapy refractory schizophrenia. Nervenarzt 75(1):79–91

    Article  PubMed  Google Scholar 

  • Shrivastava A et al (2012) Atypical antipsychotics usage in long-term follow-up of first episode schizophrenia. Indian J Psychiatry 54(3):248–252

    Article  PubMed Central  PubMed  Google Scholar 

  • Silva CER et al (2001) Estudo-piloto com clozapina em hospital público: resultados de um ano de acompanhamento. Rev Bras Psiquiatr 23:4

    Article  Google Scholar 

  • Singh NP et al (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191

    Article  CAS  PubMed  Google Scholar 

  • Swartz MA (2001) The physiology of the lymphatic system. Adv Drug Deliv Rev 50:3–20

    Article  CAS  PubMed  Google Scholar 

  • Wang CX et al (2009) Antitumor effects of polysorbate-80 coated gemcitabine polybutylcyanoacrylate nanoparticles in vitro and its pharmacodynamics in vivo on C6 glioma cells of a brain tumor model. Brain Res 1261:91–99

    Article  CAS  PubMed  Google Scholar 

  • Wu TW et al (2008) Preparation, physicochemical characterization, and antioxidant effects of quercetin nanoparticles. Int J Pharm 346:160–168

    Article  CAS  PubMed  Google Scholar 

  • Xin-Hua T et al (2011) Enhanced brain targeting of temozolomide in polysorbate-80 coated polybutylcyanoacrylate nanoparticles. Int J Nanomedicine 6:445–452

    Google Scholar 

Download references

Integrity of research and reporting

All authors report this study was approved by the Ethics Committee on Animal Use (CEUA), Federal University of Pampa (UNIPAMPA) under Protocol nº. 034/2012, which is affiliated to the Brazilian College of Animal Experimentation (COBEA). Since the experiments were conducted in accordance with the ethical and technical principles of animal experimentation established by the National Council for the Control of Animal Experimentation (CONCEA) and Law nº. 11.794 of 08 October 2008 which establishes procedures for the scientific use of animals (Brasil 2008, 2013). All animal studies were approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards.

Conflict of interest

All authors report no conflict of interest.

Author information

Authors and Affiliations

  1. Postgraduate Program in Biochemistry, Federal University of Pampa, Uruguaiana, Rio Grande do Sul, Brazil

    Angélica Aparecida da Costa Güllich, Bruna Cocco Pilar, Deise Jaqueline Ströher, Jacqueline da Costa Escobar Piccoli & Vanusa Manfredini

  2. Course of Pharmacy, Federal University of Pampa, Uruguaiana, Rio Grande do Sul, Brazil

    Ritiéle Pinto Coelho, Leandro Alex Sander Leal Galarça, Simone Machado Vieira, Jacqueline da Costa Escobar Piccoli, Sandra Elisa Haas & Vanusa Manfredini

  3. Postgraduate Lato Sensu Program in Pharmaceutical Scienses, Federal University of Pampa, Uruguaiana, Rio Grande do Sul, Brazil

    Jacqueline da Costa Escobar Piccoli & Vanusa Manfredini

  4. Postgraduate Program in Pharmaceutical Scienses, Federal University of Pampa, Uruguaiana, Rio Grande do Sul, Brazil

    Jacqueline da Costa Escobar Piccoli & Sandra Elisa Haas

  5. Laboratório de Hematologia e Citologia Clínica, Universidade Federal do Pampa – Campus Uruguaiana, BR 472, Km 585, Uruguaiana, RS, CEP: 97500-970, Brazil

    Vanusa Manfredini

Authors
  1. Angélica Aparecida da Costa Güllich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ritiéle Pinto Coelho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruna Cocco Pilar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deise Jaqueline Ströher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leandro Alex Sander Leal Galarça
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Simone Machado Vieira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jacqueline da Costa Escobar Piccoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sandra Elisa Haas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vanusa Manfredini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vanusa Manfredini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

da Costa Güllich, A.A., Coelho, R.P., Pilar, B.C. et al. Clozapine linked to nanocapsules minimizes tissue and oxidative damage to biomolecules lipids, proteins and DNA in brain of rats Wistar. Metab Brain Dis 30, 695–702 (2015). https://doi.org/10.1007/s11011-014-9621-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-014-9621-5

Keywords

Search

Navigation