Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-26T21:59:57.643Z Has data issue: false hasContentIssue false
  • English
  • Français

Deficit schizophrenia and its features are associated with PON1 Q192R genotypes and lowered paraoxonase 1 (PON1) enzymatic activity: effects on bacterial translocation

Published online by Cambridge University Press:  23 June 2020

Andressa K. Matsumoto ,
Michael Maes Open the ORCID record for Michael Maes [Opens in a new window] ,
Thitiporn Supasitthumrong Open the ORCID record for Thitiporn Supasitthumrong [Opens in a new window] ,
Annabel Maes ,
Ana P. Michelin ,
Laura de Oliveira Semeão ,
João V. de Lima Pedrão ,
Estefania G. Moreira ,
Buranee Kanchanatawan  and
Decio S. Barbosa
Andressa K. Matsumoto
Affiliation:
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
Michael Maes*
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria IMPACT Strategic Research Center, Deakin University, Geelong, Australia
Thitiporn Supasitthumrong*
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Ana P. Michelin
Affiliation:
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
Laura de Oliveira Semeão
Affiliation:
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
João V. de Lima Pedrão
Affiliation:
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
Estefania G. Moreira
Affiliation:
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
Buranee Kanchanatawan
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Decio S. Barbosa
Affiliation:
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
*
*Thitiporn Supasitthumrong and Michael Maes, MD, PhD Email [email protected], [email protected]
*Thitiporn Supasitthumrong and Michael Maes, MD, PhD Email [email protected], [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology.

Methods

In this case-control study, Thai women and men, aged 18 to 65 years, were divided in DS (n = 40) and NDS (n = 40) and were compared to controls (n = 40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and immunoglobulin A (IgA) levels responses directed to Gram-negative bacteria were measured.

Results

DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers.

Conclusions

The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing toward greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

Keywords

Deficit schizophreniaantioxidantsbacteriainflammationoxidative and nitrosative stress
Type
Original Research
Information
CNS Spectrums , Volume 26 , Issue 4 , August 2021 , pp. 406 - 415
Copyright
© The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

Buranee Kanchanatawan and Decio S. Barbosa shared senior authorship

References

Wu, Y, Yao, YG, Luo, XJ. SZDB: a database for schizophrenia genetic research. Schizophr Bull. 2017;43(2):459–471.Google ScholarPubMed
Kanchanatawan, B, Sriswasdi, S, Thika, S, et al. Deficit schizophrenia is a discrete diagnostic category defined by neuro-immune and neurocognitive features: results of supervised machine learning. Metabol Brain Dis. 2018;33(4):1053–1067.CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Sriswasdi, S, Thika, S, et al. Towards a new classification of stable phase schizophrenia into major and simple neuro-cognitive psychosis: Results of unsupervised machine learning analysis. J Evaluat Clin Pract. 2018;24(4):879–891.CrossRefGoogle ScholarPubMed
Berrios, G, Luque, R. Schizophrenia: a conceptual history. Int J Psychol Psychol Ther. 2003;3(2):111–140.Google Scholar
Maes, M, Meltzer, HY, Bosmans, E. Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand. 1994;89(5):346–351.CrossRefGoogle ScholarPubMed
Maes, M, Delange, J, Ranjan, R, et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res. 1997;66(1):1–11.CrossRefGoogle ScholarPubMed
Brinholi, F, Noto, C, Maes, M, et al. Lowered paraoxonase 1 (PON1) activity is associated with increased cytokine levels in drug naïve first episode psychosis. Schizophr Res. 2015;166CrossRefGoogle ScholarPubMed
Kanchanatawan, B, Sirivichayakul, S, Ruxrungtham, K, et al. Deficit schizophrenia is characterized by defects in IgM-mediated responses to tryptophan catabolites (TRYCATs): a paradigm shift towards defects in natural self-regulatory immune responses coupled with mucosa-derived TRYCAT pathway activation. Mol Neurobiol. 2018;55(3):2214–2226.CrossRefGoogle ScholarPubMed
Sirivichayakul, S, Kanchanatawan, B, Thika, S, Carvalho, AF, Maes, M. Eotaxin, an endogenous cognitive deteriorating chemokine (ECDC), is a major contributor to cognitive decline in normal people and to executive, memory, and sustained attention deficits, formal thought disorders, and psychopathology in schizophrenia patients. Neurotox Res. 2019;35(1):122–138.CrossRefGoogle Scholar
Sirivichayakul, S, Kanchanatawan, B, Thika, S, Carvalho, AF, Maes, M. A new schizophrenia model: immune activation is associated with the induction of different neurotoxic products which together determine memory impairments and schizophrenia symptom dimensions. CNS Neurol Disord Drug Targets. 2019;18(2):124–140.CrossRefGoogle ScholarPubMed
Maes, M, Sirivichayakul, S, Kanchanatawan, B, Vodjani, A. Upregulation of the intestinal paracellular pathway with breakdown of tight and adherens junctions in deficit schizophrenia. Mol Neurobiol. 2019;56(10):7056–7073.CrossRefGoogle ScholarPubMed
Maes, M, Sirivichayakul, S, Kanchanatawan, B, Vodjani, A. Breakdown of the paracellular tight and adherens junctions in the gut and blood brain barrier and damage to the vascular barrier in patients with deficit schizophrenia. Neurotox Res. 2019;36(2):306–322.CrossRefGoogle Scholar
Roomruangwong, C, Noto, C, Kanchanatawan, B, et al. The role of aberrations in the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: the IRS-CIRS theory of schizophrenia. Mol Neurobiol. 2019; 1559–1182Google ScholarPubMed
Maes, M, Kanchanatawan, B, Sirivichayakul, S, Carvalho, AF. In schizophrenia, increased plasma IgM/IgA responses to gut commensal bacteria are associated with negative symptoms, neurocognitive impairments, and the deficit phenotype. Neurotox Res. 2019;35(3):684–698.CrossRefGoogle ScholarPubMed
Maes, M, Sirivichayakul, S, Kanchanatawan, B, Carvalho, A. In schizophrenia, psychomotor retardation is associated with executive and memory impairments, negative and psychotic symptoms, neurotoxic immune products and lower natural IgM to malondialdehyde. World J Biol Psychiatry. 2019;Google Scholar
Anderson, G, Maes, M. Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:5–19.CrossRefGoogle ScholarPubMed
Anderson, G, Berk, M, Dodd, S, et al. Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:1–4.CrossRefGoogle ScholarPubMed
Davis, J, Moylan, S, Harvey, BH, Maes, M, Berk, M. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Austr N Z J Psychiatry. 2014;48(6):512–529.CrossRefGoogle ScholarPubMed
Davis, J, Eyre, H, Jacka, FN, et al. A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis. Neurosci Biobehav Rev. 2016;65:185–194.CrossRefGoogle ScholarPubMed
Moreira, EG, Boll, KM, Correia, DG, Soares, JF, Rigobello, C, Maes, M. Why should psychiatrists and neuroscientists worry about paraoxonase 1? Curr Neuropharmacol. 2019;17(11):1004–1020.CrossRefGoogle ScholarPubMed
Moreira, EG, Correia, DG, Bonifacio, KL, et al. Lowered PON1 activities are strongly associated with depression and bipolar disorder, recurrence of (hypo)mania and depression, increased disability and lowered quality of life. World J Biol Psychiatry. 2019;20(5):368–380.CrossRefGoogle ScholarPubMed
Bayrak, A, Bayrak, T, Bodur, E, Kilinc, K, Demirpence, E. The effect of HDL-bound and free PON1 on copper-induced LDL oxidation. Chem Biol Interact. 2016;257:141–146.CrossRefGoogle ScholarPubMed
Atagun, MI, Tunc, S, Alisik, M, Erel, O. Phenotypic variants of paraoxonase Q192R in bipolar disorder, depression and schizophrenia. Turkish J Psychiatry. 2018;29(2):79–86.Google Scholar
Richter, RJ, Jarvik, GP, Furlong, CE. Determination of paraoxonase 1 status without the use of toxic organophosphate substrates. Circulat Cardiovasc Genet. 2008;1(2):147–152.CrossRefGoogle ScholarPubMed
Marsillach, J, Camps, J, Ferre, N, et al. Paraoxonase-1 is related to inflammation, fibrosis and PPAR delta in experimental liver disease. BMC Gastroenterol. 2009;9:3CrossRefGoogle ScholarPubMed
Bar-Rogovsky, H, Hugenmatter, A, Tawfik, DS. The evolutionary origins of detoxifying enzymes: the mammalian serum paraoxonases (PONs) relate to bacterial homoserine lactonases. J Biol Chem. 2013;288(33):23914–23927.CrossRefGoogle ScholarPubMed
Kirkpatrick, B, Buchanan, RW, McKenney, PD, Alphs, LD, Carpenter, WT Jr. The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 1989;30(2):119–123.CrossRefGoogle Scholar
Kittirattanapaiboon, P, Khamwongpin, M. The Validity of the Mini International Neuropsychiatric Interview (M.I.N.I)-Thai version. 2005.Google Scholar
Andreasen, NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl. 1989;(7):49–58.CrossRefGoogle ScholarPubMed
Kay, SR, Fiszbein, A, Opler, LA. The Positive and Negative Syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276.CrossRefGoogle Scholar
Overall, JE, Gorham, DR. The Brief Psychiatric Rating scale. Psychol Rep. 1962;10(3):799–812.CrossRefGoogle Scholar
Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.CrossRefGoogle ScholarPubMed
Geffard, M, Bodet, D, Martinet, Y, Dabadie, M.-P. Detection of the specific IgM and IgA circulating in sera of multiple sclerosis patients: interest and perspectives. Immunoanal Biol Special. 2002;17:302–310.Google Scholar
Maes, M, Kubera, M, Leunis, JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008;29(1):117–124.Google Scholar
Benjamini, Y, Hochberg, Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J Royal Statist Soc B. 1995;57:289–300.Google Scholar
Ringle, CM, Wende, S, Becker, J-M. SmartPLS 3. Bönningstedt, Germany: SmartPLS; 2015. http://www.smartpls.com.Google Scholar
Kucukali, CI, Aydin, M, Ozkok, E, et al. Paraoxonase-1 55/192 genotypes in schizophrenic patients and their relatives in Turkish population. Psychiatr Genet. 2008;18(6):289–294.CrossRefGoogle ScholarPubMed
Mackness, B, Mackness, MI, Arrol, S, Turkie, W, Durrington, PN. Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Lett. 1998;423(1):57–60.CrossRefGoogle ScholarPubMed
Roomruangwong, C, Barbosa, DS, Matsumoto, AK, et al. Activated neuro-oxidative and neuro-nitrosative pathways at the end of term are associated with inflammation and physio-somatic and depression symptoms, while predicting outcome characteristics in mother and baby. J Affect Disord. 2017;223:49–58.CrossRefGoogle ScholarPubMed
Coombes, RH, Crow, JA, Dail, M, et al. Relationship of human paraoxonase-1 serum activity and genotype with atherosclerosis in individuals from the Deep South. Pharmacogenet Genom. 2011;21(12):867–875.CrossRefGoogle ScholarPubMed
Suehiro, T, Nakamura, T, Inoue, M, et al. A polymorphism upstream from the human paraoxonase (PON1) gene and its association with PON1 expression. Atherosclerosis. 2000;150(2):295–298.CrossRefGoogle ScholarPubMed
Zhou, Z, Wu, H, Zhou, J, Xue, S. Activity of serum paraoxonase and its polymorphism in healthy Chinese of Shanghi. Chinese J Preventive Med. 2000;34:20–21.Google Scholar
Seow, DC, Gao, Q, Yap, P, et al. Profile of the paraoxonase 1 (PON1) gene 192Q/R polymorphism and clinical associations among older Singaporean Chinese with Alzheimer’s and mixed dementia. Dementia Geriatr Cogn Disord Extra. 2016;6(1):43–54.CrossRefGoogle ScholarPubMed
Ringen, PA, Engh, JA, Birkenaes, AB, Dieset, I, Andreassen, OA. Increased mortality in schizophrenia due to cardiovascular disease—a non-systematic review of epidemiology, possible causes, and interventions. Front Psychiatry. 2014;5:137CrossRefGoogle ScholarPubMed
Hernandez-Diaz, Y, Tovilla-Zarate, CA, Juarez-Rojop, IE, et al. Effects of paraoxonase 1 gene polymorphisms on heart diseases: systematic review and meta-analysis of 64 case–control studies. Medicine. 2016;95(44):e5298CrossRefGoogle ScholarPubMed
Saadat, M. Paraoxonase 1 genetic polymorphisms and susceptibility to breast cancer: a meta-analysis. Cancer Epidemiol. 2011;36:e101–e103.CrossRefGoogle ScholarPubMed
Zhang, M, Xiong, H, Fang, L, et al. Paraoxonase 1 (PON1) Q192R gene polymorphism and cancer risk: a meta-analysis based on 30 publications. Asian Pacific J Cancer Prevent. 2015;16(10):4457–4463.CrossRefGoogle ScholarPubMed
Zhuo, C, Triplett, PT. Association of schizophrenia with the risk of breast cancer incidence: a meta-analysis. JAMA Psychiatry. 2018;75(4):363–369.CrossRefGoogle ScholarPubMed
Schoepf, D, Potluri, R, Uppal, H, Natalwala, A, Narendran, P, Heun, R. Type-2 diabetes mellitus in schizophrenia: increased prevalence and major risk factor of excess mortality in a naturalistic 7-year follow-up. Eur Psychiatry. 2012;27(1):33–42.CrossRefGoogle Scholar
van den Berg, SW, Jansen, EH, Kruijshoop, M, et al. Paraoxonase 1 phenotype distribution and activity differs in subjects with newly diagnosed Type 2 diabetes (the CODAM Study). Diab Med. 2008;25(2):186–193.CrossRefGoogle Scholar
Alharbi, K, Alharbi, FK, Ghneim, HK, et al. Amendment of amino acid in Q192R genetic polymorphism of paraoxonase 1 is a conventional risk factor for type 2 diabetes mellitus in the Saudi population. Int J Clin Exp Med 2016;9:16605–16612.Google Scholar
Luo, JQ, Ren, H, Liu, MZ, Fang, PF, Xiang, DX. European versus Asian differences for the associations between paraoxonase-1 genetic polymorphisms and susceptibility to type 2 diabetes mellitus. J Cell Mol Med. 2018;22(3):1720–1732.CrossRefGoogle ScholarPubMed
Noto, C, Ota, VK, Gadelha, A, et al. Oxidative stress in drug naive first episode psychosis and antioxidant effects of risperidone. J Psychiatr Res. 2015;68:210–216.CrossRefGoogle ScholarPubMed
Pavăl, D, Nemeș, B, Rusu, RL, Dronca, E. Genotype-phenotype analysis of paraoxonase 1 in schizophrenic patients treated with atypical antipsychotics. Clin Psychopharmacol Neurosci. 2018;16(1):32–38.CrossRefGoogle ScholarPubMed
Gupta, N, Singh, S, Maturu, VN, Sharma, YP, Gill, KD. Paraoxonase 1 (PON1) polymorphisms, haplotypes and activity in predicting cad risk in North-West Indian Punjabis. PloS One. 2011;6(5):e17805CrossRefGoogle ScholarPubMed
Kalayasiri, R, Kraijak, K, Mutirangura, A, Maes, M. Paranoid schizophrenia and methamphetamine-induced paranoia are both characterized by a similar LINE-1 partial methylation profile, which is more pronounced in paranoid schizophrenia. Schizophr Res. 2019;208:221–227.CrossRefGoogle ScholarPubMed
Karlsson, H, Kontush, A, James, RW. Functionality of HDL: antioxidation and detoxifying effects. Handbook Exp Pharmacol. 2015;224:207–228.CrossRefGoogle ScholarPubMed
Huang, Y, Wu, Z, Riwanto, M, et al. Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. J Clin Investigat. 2013;123(9):3815–3828.CrossRefGoogle Scholar
Aybey, A, Demirkan, E. Inhibition of Pseudomonas aeruginosa biofilm formation and motilities by human serum paraoxonase (hPON1). AIMS Microbiol. 2016;2:388–401.CrossRefGoogle Scholar
Koul, S, Kalia, VC. Multiplicity of quorum quenching enzymes: a potential mechanism to limit quorum sensing bacterial population. Indian J Microbiol. 2017;57(1):100–108.CrossRefGoogle ScholarPubMed
Elias, M, Tawfik, DS. Divergence and convergence in enzyme evolution: parallel evolution of paraoxonases from quorum-quenching lactonases. J Biol Chem. 2012;287(1):11–20.CrossRefGoogle ScholarPubMed
Draganov, DI, Teiber, JF, Speelman, A, Osawa, Y, Sunahara, R, La Du, BN. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005;46(6):1239–1247.CrossRefGoogle ScholarPubMed
Marsillach, J, Mackness, B, Mackness, M, et al. Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Rad Biol Med. 2008;45(2):146–157.CrossRefGoogle ScholarPubMed
Veesenmeyer, JL, Hauser, AR, Lisboa, T, Rello, J. Pseudomonas aeruginosa virulence and therapy: evolving translational strategies. Critic care Med. 2009;37(5):1777–1786.CrossRefGoogle ScholarPubMed
Stoyanov, D. The endophenotype project and the validation theory: integration of neurobiology and psychiatry. Folia Med. 2010;52:18–25.Google ScholarPubMed
Maes, M, Vojdani, A, Geffard, M, et al. Schizophrenia phenomenology comprises a bifactorial general severity and a single-group factor, which are differently associated with neurotoxic immune and immune-regulatory pathways. Biomol Concepts. 2019;10(1):209–225.CrossRefGoogle Scholar
Kanchanatawan, B, Sriswasdi, S, Maes, M. Supervised machine learning to decipher the complex associations between neuro-immune biomarkers and quality of life in schizophrenia. Metab Brain Dis. 2019;34(1):267–282.CrossRefGoogle Scholar
Gottesman, II, Gould, TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–645.CrossRefGoogle ScholarPubMed
Snezhnevsky, AV, Vartanian, ME. The forms of schizophrenia and their biological correlates. In: Himwich, HE, ed. Biochemistry, Schizophrenia and Affective Illnesses. Baltimore, MD: Williams & Wilkins; 1970:1–28.Google Scholar