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Influence of prebiotic intake on olanzapine-mediated weight gain, central receptors, peripheral biomarkers, and gut microbiota
S14 it was also observed, that psychotropic drugs are able to directly inhibit certain enzymes [2-4]. Different concentrations (0.00375 mg/ml - 3.75 mg/ml) of choline alfoscerate had no influence on LE activity (p = 0.33). Cerebrolysin at concentrations from 0.043 mg/ml to 2.15 mg/ml also had no influence on LE activity, however, at concentration 4.3 mg/ml, which corresponds to a double maximum dose, cerebrolysin had a potentiating effect on LE, whose activity significantly increased by 17.5% compared to control (p o0.01). The activating effect of cerebrolysin on LE activity can be explained by the effect of substrate activation. In addition to oligopeptides described previously [5], cerebrolysin (a mixture of oligopeptides), can be classified as such activating substrates for LE. Conclusion: Thus, it has been shown that psychotropic drugs such as chlorpromazine and imipramine have an inhibitory effect on LE activity in an in vitro experiment, while nootropic cerebrolysin can activate LE. The obtained data indicate that these drugs, used in the treatment of mental illness, can influence inflammatory response, which is important in the pathogenesis of mental disorders.
References [1] Kliushnik, T.P., Zozulya, S.A., Androsova, L.V., Sarmanova, Z.V., Otman, I.N., Dupin, A.M., Panteleyeva, G.P., Oleichik, I.V., Abramova, L.I., Stolyarova, S.A., Shipilova, E. S., Borisova, O.A., 2014. Immunological monitoring of endogenous attack-like psychoses. Journal of Neurology and Psychiatry n.а. S. S. Korsakov 114(2), 37-41. (In Russ.) [2] Jasmin, G., 1957. Anti-inflammatory properties of chlorpromazine. Arch Int Pharmacodyn Ther 112(1-2), 1-7. [3] Tangri, K.K., Saxena, P.R., Seth, P.K., Bhargava, K.P., 1966. Anti-inflammatory activity of imipramine and congeners. Biochem Pharmacol 15(7), 825-831. [4] Peltonen, I., Männistö, P.T., 2011. Effects of diverse psychopharmacological substances on the activity of brain prolyl oligopeptidase. Basic Clin Pharmacol Toxicol 108(1), 46-54. [5] Lestienne, P., Bieth, J.G., 1980. Activation of human leukocyte elastase activity by excess substrate, hydrophobic solvents, and ionic strength. J Biol Chem 255(19), 9289-9294. http://dx.doi.org/10.1016/j.euroneuro.2017.12.032
P.1.015 Influence of prebiotic intake on olanzapinemediated weight gain, central receptors, peripheral biomarkers, and gut microbiota A. Kaon, B. Lennox, P. Burnet University of Oxford, Department of Psychiatry, Oxford, United Kingdom Olanzapine is the first-line antipsychotic treatment for schizophrenia, but often leads to secondary health concerns such as metabolic syndrome and weight gain. Studies in rats
have shown that chronic olanzapine administration induces weight gain [1] and reduces hippocampal glutamate N-methyl-D-Aspartate receptor (NMDAR) levels, the latter which may hinder the recovery of cognitive function in schizophrenia patients. We have shown that dietary augmentation of beneficial gut bacteria using the commercially available prebiotic Bimuno™ galacto-oligosaccharides (B-GOSs) increases central levels of NMDAR subunits in rodents [2,3]. The aim of this study was to determine whether the effects of olanzapine on weight gain and peripheral effects are influenced by B-GOSs intake in rats. Adult female Sprague-Dawley rats were provided with a B-GOSs (0.5g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. Weight gain and water intake were monitored daily. We determined whether B-GOSs influenced olanzapine-associated weight gain, and central NMDAR and serotonin receptor expression. Circulating levels of acetate, IL-1β, IL-8 and TNFα as well as liver acetyl-CoA Carboxylase (ACC), white adipose tissue acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Two-way ANOVAs were used to analyse all data, with repeated measures included to explore weight gain. Olanzapine induced significant weight gain (p o 0.001) compared to saline-controls, an effect driven by significant weight gain in water/olanzapine rats on days 8-14 (po0.05). Significant weight gain was not observed in olanzapine-injected animals on the B-GOS diet compared to those receiving water (p = 0.013). This prebiotic effect did not alter cortical 5-HT2AR blockade. Overall olanzapine treatment significantly increased cortical GluN1 (p = 0.002) in B-GOSs-fed rats. Significant effect of treatment was observed on hippocampal GluN1 mRNA abundance (p = 0.034), where olanzapine significantly increased (+ 17%) levels in the absence of B-GOSs (p = 0.040). Plasma acetate concentrations increased following B-GOSs or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOSs. Co-administration of B-GOSs and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOSs elevated faecal Bifidobacterium Spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOSs, was without effect. The current study demonstrates a potential strategy to reduce olanzapine-mediated weight gain in schizophrenia without compromising a key central pharmacological action of this antipsychotic. We also demonstrate a NMDAR augmenting effect, supporting a potential pro-cognitive effect of the prebiotic. Our data also implies that elevated TNFα in B-GOSs/olanzapine rats may contribute to the reduction in olanzapine-induced weight gain as pro-inflammatory TNFα is a recognised appetite suppressant. These data suggest that inclusion of B-GOSs as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis.
Abstracts of the ENCP Workshop for Junior Scientists in Europe, 2018
References [1] van der Zwaal, E.M., Janhunen, S.K., la Fleur, S.E., Adan, R.A., 2014. Modelling olanzapine-induced weight gain in rats. Int J Neuropsychopharmacol 17, 169-186. [2] Williams, S., Chen, L., Savignac, H.M., Tzortzis, G., Anthony, D.C., et al., 2016. Neonatal prebiotic (BGOS) supplementation increases the levels of synaptophysin, GluN2A-subunits and BDNF proteins in the adult rat hippocampus. Synapse 70, 121-124. [3] Savignac, H.M., Corona, G., Mills, H., Chen, L., Spencer, J.P., et al., 2013. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine. Neurochem Int 63, 756-764. http://dx.doi.org/10.1016/j.euroneuro.2017.12.033
P.1.016 Molecular linking of influenza infection to cellular pathology of protein misassembly: the case of Disrupted-in-Schizophrenia 1 (DISC1) R. Marreirosn,1, I. Prikulis1, A. Müller-Schiffmann1, A.R. Moreira2, S. Sahu2, I. Soloviev2, S. Selvarajah2, V. Lingappa2, C. Korth1 1
Heinrich Heine Universität Düsseldorf, Institut für Neuropathologie-14.79/3, Duesseldorf, Germany 2 Prosetta Biosciences- Inc., Prosetta Biosciences- Inc., San Francisco, USA Chronic mental illnesses such as schizophrenia or recurrent affective disorders are heterogeneous in their biological causes behind the clinical, syndromatic diagnosis. Viral infection has been linked to chronic mental illnesses both by direct mechanisms and indirect mechanisms through immune stimulation. For example, studies showed that intrauterine influenza infection could be a risk factor for chronic mental illness [1]. It is also established that viral infection can lead to a change in proteostasis impairing regulatory protein networks and leading to disease. The most dramatic consequences of disrupted proteostasis are the so-called protein misfolding diseases that show as a phenotypical hallmark, microscopically visible deposits of one or several proteins, and cell degeneration. More subtle forms of proteostatic imbalance exist where protein deposits are not microscopically visible and the neurons do not die but remain functionally impaired, for example in some forms of chronic mental illness such as schizophrenia [2]. We previously reported insoluble Disrupted-in-schizophrenia 1 (DISC1) protein in a subpopulation of patients with chronic mental illness [3]. This gene/protein is involved in vulnerability to chronic mental disorders, and was discovered mutant and segregating in a large Scottish pedigree with a chromosomal translocation leading to a 3′ truncation of the gene [4]. Subsequent genetic association studies in multiple populations of different ethnicities also support the involvement of this protein in mental illness. For the present study, our hypothesis was that influenza infection could cause significant long-term impairments of specific proteostatic pathways leading to aggregated DISC1
S15
protein in chronic mental illness patients [5]. Neuroblastoma cell lines expressing inducible full-length, non-mutant DISC1 protein were infected with WSN33 influenza (H1N1 strain). The effect of viral infection was investigated by immunocytochemistry, biochemical and functional assays. Furthermore, infected mice with WSN33 influenza where investigated for insoluble DISC1 deposits by immunohistochemistry. Antiviral drugs were tested in order to reverse the influenza-induced DISC1 aggregates. Influenza infection of cell lines induced DISC1 misassembly but not misassembly of the protein TDP43 known to be mislocalized in ALS, but not in mental illness or influenza, and therefore serving as a control for specificity of DISC1 misassembly upon influenza infection in cellular models. Appearance of DISC1 deposits was dependent on infectious influenza virus titer, and the infection time. Functional consequences of influenza-induced DISC1 misassembly will be reported, as well as our investigations of influenza-infected mice that are still ongoing. We conclude that influenza infection leads to a very specific proteostatic change, including the misassembly of DISC1, which has functional consequences for dopamine homeostasis. Thus a selective reprogramming of cellular homeostasis, as measured by proteostasis, may be a novel molecular mechanism by which influenza infection can lead to brain disease.
References [1] Limosin, F., Rouillon, F., Payan, C., Cohen, J.M., Strub, N., 2003. Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand. 107, 331-335. [2] Korth, C., 2012. Aggregated proteins in chronic mental diseases: DISC1opathies. Prion, 6, 1-8. [3] Leliveld, S.R., Bader, V., Hendriks, P., Prikulis, I., Sajnani, G., Requena, J.R, Korth, C. 2008. Insolubility of disrupted-inschizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci. 28(15), 3839-3845. [4] Millar, J.K., Wilson-Annan ,J.C., Anderson, S., Christie, S., Taylor, M.S., Semple, C.A. et al., 2000. Disruption of two novel genes by a translocation co-segregating with schizophrenia.Hum Mol Genet 9, 1415–1423. [5] Marreiros, R., Müller-Schiffmann, A., Bader, V., Selvarajah, S., Day, D., Lingappa, V.R., Korth, C., 2015. Viral Capsid Assembly as a Model for Protein Aggregation Diseases: Active Processes Catalyzed by Cellular Assembly Machines Comprising Novel Drug Targets. Virus Research 207, 155-164. http://dx.doi.org/10.1016/j.euroneuro.2017.12.034
P.1.017 New link between inflammation and schizophrenia: IgG with nuclease activity E. Ermakovn,1, O. Zaharova2, S. Ivanova3, V. Buneva2, G. Nevinsky2 1
Novosibirsk State University, Department of Natural Sciences, Novosibirsk, Russia
References [1] Kliushnik, T.P., Zozulya, S.A., Androsova, L.V., Sarmanova, Z.V., Otman, I.N., Dupin, A.M., Panteleyeva, G.P., Oleichik, I.V., Abramova, L.I., Stolyarova, S.A., Shipilova, E. S., Borisova, O.A., 2014. Immunological monitoring of endogenous attack-like psychoses. Journal of Neurology and Psychiatry n.а. S. S. Korsakov 114(2), 37-41. (In Russ.) [2] Jasmin, G., 1957. Anti-inflammatory properties of chlorpromazine. Arch Int Pharmacodyn Ther 112(1-2), 1-7. [3] Tangri, K.K., Saxena, P.R., Seth, P.K., Bhargava, K.P., 1966. Anti-inflammatory activity of imipramine and congeners. Biochem Pharmacol 15(7), 825-831. [4] Peltonen, I., Männistö, P.T., 2011. Effects of diverse psychopharmacological substances on the activity of brain prolyl oligopeptidase. Basic Clin Pharmacol Toxicol 108(1), 46-54. [5] Lestienne, P., Bieth, J.G., 1980. Activation of human leukocyte elastase activity by excess substrate, hydrophobic solvents, and ionic strength. J Biol Chem 255(19), 9289-9294. http://dx.doi.org/10.1016/j.euroneuro.2017.12.032
P.1.015 Influence of prebiotic intake on olanzapinemediated weight gain, central receptors, peripheral biomarkers, and gut microbiota A. Kaon, B. Lennox, P. Burnet University of Oxford, Department of Psychiatry, Oxford, United Kingdom Olanzapine is the first-line antipsychotic treatment for schizophrenia, but often leads to secondary health concerns such as metabolic syndrome and weight gain. Studies in rats
have shown that chronic olanzapine administration induces weight gain [1] and reduces hippocampal glutamate N-methyl-D-Aspartate receptor (NMDAR) levels, the latter which may hinder the recovery of cognitive function in schizophrenia patients. We have shown that dietary augmentation of beneficial gut bacteria using the commercially available prebiotic Bimuno™ galacto-oligosaccharides (B-GOSs) increases central levels of NMDAR subunits in rodents [2,3]. The aim of this study was to determine whether the effects of olanzapine on weight gain and peripheral effects are influenced by B-GOSs intake in rats. Adult female Sprague-Dawley rats were provided with a B-GOSs (0.5g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. Weight gain and water intake were monitored daily. We determined whether B-GOSs influenced olanzapine-associated weight gain, and central NMDAR and serotonin receptor expression. Circulating levels of acetate, IL-1β, IL-8 and TNFα as well as liver acetyl-CoA Carboxylase (ACC), white adipose tissue acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Two-way ANOVAs were used to analyse all data, with repeated measures included to explore weight gain. Olanzapine induced significant weight gain (p o 0.001) compared to saline-controls, an effect driven by significant weight gain in water/olanzapine rats on days 8-14 (po0.05). Significant weight gain was not observed in olanzapine-injected animals on the B-GOS diet compared to those receiving water (p = 0.013). This prebiotic effect did not alter cortical 5-HT2AR blockade. Overall olanzapine treatment significantly increased cortical GluN1 (p = 0.002) in B-GOSs-fed rats. Significant effect of treatment was observed on hippocampal GluN1 mRNA abundance (p = 0.034), where olanzapine significantly increased (+ 17%) levels in the absence of B-GOSs (p = 0.040). Plasma acetate concentrations increased following B-GOSs or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOSs. Co-administration of B-GOSs and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOSs elevated faecal Bifidobacterium Spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOSs, was without effect. The current study demonstrates a potential strategy to reduce olanzapine-mediated weight gain in schizophrenia without compromising a key central pharmacological action of this antipsychotic. We also demonstrate a NMDAR augmenting effect, supporting a potential pro-cognitive effect of the prebiotic. Our data also implies that elevated TNFα in B-GOSs/olanzapine rats may contribute to the reduction in olanzapine-induced weight gain as pro-inflammatory TNFα is a recognised appetite suppressant. These data suggest that inclusion of B-GOSs as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis.
Abstracts of the ENCP Workshop for Junior Scientists in Europe, 2018
References [1] van der Zwaal, E.M., Janhunen, S.K., la Fleur, S.E., Adan, R.A., 2014. Modelling olanzapine-induced weight gain in rats. Int J Neuropsychopharmacol 17, 169-186. [2] Williams, S., Chen, L., Savignac, H.M., Tzortzis, G., Anthony, D.C., et al., 2016. Neonatal prebiotic (BGOS) supplementation increases the levels of synaptophysin, GluN2A-subunits and BDNF proteins in the adult rat hippocampus. Synapse 70, 121-124. [3] Savignac, H.M., Corona, G., Mills, H., Chen, L., Spencer, J.P., et al., 2013. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine. Neurochem Int 63, 756-764. http://dx.doi.org/10.1016/j.euroneuro.2017.12.033
P.1.016 Molecular linking of influenza infection to cellular pathology of protein misassembly: the case of Disrupted-in-Schizophrenia 1 (DISC1) R. Marreirosn,1, I. Prikulis1, A. Müller-Schiffmann1, A.R. Moreira2, S. Sahu2, I. Soloviev2, S. Selvarajah2, V. Lingappa2, C. Korth1 1
Heinrich Heine Universität Düsseldorf, Institut für Neuropathologie-14.79/3, Duesseldorf, Germany 2 Prosetta Biosciences- Inc., Prosetta Biosciences- Inc., San Francisco, USA Chronic mental illnesses such as schizophrenia or recurrent affective disorders are heterogeneous in their biological causes behind the clinical, syndromatic diagnosis. Viral infection has been linked to chronic mental illnesses both by direct mechanisms and indirect mechanisms through immune stimulation. For example, studies showed that intrauterine influenza infection could be a risk factor for chronic mental illness [1]. It is also established that viral infection can lead to a change in proteostasis impairing regulatory protein networks and leading to disease. The most dramatic consequences of disrupted proteostasis are the so-called protein misfolding diseases that show as a phenotypical hallmark, microscopically visible deposits of one or several proteins, and cell degeneration. More subtle forms of proteostatic imbalance exist where protein deposits are not microscopically visible and the neurons do not die but remain functionally impaired, for example in some forms of chronic mental illness such as schizophrenia [2]. We previously reported insoluble Disrupted-in-schizophrenia 1 (DISC1) protein in a subpopulation of patients with chronic mental illness [3]. This gene/protein is involved in vulnerability to chronic mental disorders, and was discovered mutant and segregating in a large Scottish pedigree with a chromosomal translocation leading to a 3′ truncation of the gene [4]. Subsequent genetic association studies in multiple populations of different ethnicities also support the involvement of this protein in mental illness. For the present study, our hypothesis was that influenza infection could cause significant long-term impairments of specific proteostatic pathways leading to aggregated DISC1
S15
protein in chronic mental illness patients [5]. Neuroblastoma cell lines expressing inducible full-length, non-mutant DISC1 protein were infected with WSN33 influenza (H1N1 strain). The effect of viral infection was investigated by immunocytochemistry, biochemical and functional assays. Furthermore, infected mice with WSN33 influenza where investigated for insoluble DISC1 deposits by immunohistochemistry. Antiviral drugs were tested in order to reverse the influenza-induced DISC1 aggregates. Influenza infection of cell lines induced DISC1 misassembly but not misassembly of the protein TDP43 known to be mislocalized in ALS, but not in mental illness or influenza, and therefore serving as a control for specificity of DISC1 misassembly upon influenza infection in cellular models. Appearance of DISC1 deposits was dependent on infectious influenza virus titer, and the infection time. Functional consequences of influenza-induced DISC1 misassembly will be reported, as well as our investigations of influenza-infected mice that are still ongoing. We conclude that influenza infection leads to a very specific proteostatic change, including the misassembly of DISC1, which has functional consequences for dopamine homeostasis. Thus a selective reprogramming of cellular homeostasis, as measured by proteostasis, may be a novel molecular mechanism by which influenza infection can lead to brain disease.
References [1] Limosin, F., Rouillon, F., Payan, C., Cohen, J.M., Strub, N., 2003. Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand. 107, 331-335. [2] Korth, C., 2012. Aggregated proteins in chronic mental diseases: DISC1opathies. Prion, 6, 1-8. [3] Leliveld, S.R., Bader, V., Hendriks, P., Prikulis, I., Sajnani, G., Requena, J.R, Korth, C. 2008. Insolubility of disrupted-inschizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci. 28(15), 3839-3845. [4] Millar, J.K., Wilson-Annan ,J.C., Anderson, S., Christie, S., Taylor, M.S., Semple, C.A. et al., 2000. Disruption of two novel genes by a translocation co-segregating with schizophrenia.Hum Mol Genet 9, 1415–1423. [5] Marreiros, R., Müller-Schiffmann, A., Bader, V., Selvarajah, S., Day, D., Lingappa, V.R., Korth, C., 2015. Viral Capsid Assembly as a Model for Protein Aggregation Diseases: Active Processes Catalyzed by Cellular Assembly Machines Comprising Novel Drug Targets. Virus Research 207, 155-164. http://dx.doi.org/10.1016/j.euroneuro.2017.12.034
P.1.017 New link between inflammation and schizophrenia: IgG with nuclease activity E. Ermakovn,1, O. Zaharova2, S. Ivanova3, V. Buneva2, G. Nevinsky2 1
Novosibirsk State University, Department of Natural Sciences, Novosibirsk, Russia