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Gene expression in the brain of adult rats with behavioural alterations caused by neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin
P.1.a. Basic and clinical neuroscience − Genetics and epigenetics [5] Park, H.R., Lee, J.M., Moon, H.E., Lee, D.S., Kim, B.N., Kim, J., et al., 2016. A Short Review on the Current Understanding of Autism Spectrum Disorders. Exp Neurobiol, 25:1−13. doi:10.5607/ en.2016.25.1.1.
P.1.a.018 Gene expression in the brain of adult rats with behavioural alterations caused by neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin N.A. Krupina1 ° , E.A. Zubkov2 , E.V. Orshanskaya3 , Y.A. Zorkina2 , N.N. Khlebnikova1 1 Institute of General Pathology and Pathophysiology, Laboratory of General Pathology of the Nervous System, Moscow, Russia; 2 V. P. Serbsky State Research Center for Social and Forensic Psychiatry, Department of Fundamental and Applied Neurobiology, Moscow, Russia; 3 Institute of General Pathology and Pathophysiology, Department of General Pathology, Moscow, Russia Background: Depression, anxiety and aggressiveness represent a frequent long-term outcome of neurodevelopmental disorders. Clinical overlap of these disorders suppose that they share genetic risk factors [1,2]. Serine proteases dipeptidyl peptidase IV (DPP4, EC 3.4.14.5) and prolyl endopeptidase (PREP; EC 3.4.21.26) are involved in the pathophysiology of emotional and mood disorders [3]. Recently, we have revealed that adolescent and adult rats exhibit an increase in anxiety and depressionrelated behaviors with disinhibited aggression upon mild stress provocation after neonatal administration of two competitive, selective DPP4 inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg) [4]. Diprotin A exhibited a more significant negative impact on the animals’ behaviors compared to sitagliptin. These findings demonstrated the involvement of DPP4 in the genesis of emotional and motivational disorders. Objective: To study gene expression of DPP4, PREP, monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and serotonin transporter (SERT) in the brain structures of adult rats with emotional and motivational disorders induced by neonatal administration of DPP4 inhibitors sitagliptin and diprotin A. Methods: Sitagliptin (4 mg/kg) and diprotin A (2 mg/kg) were intraperitoneally administered to the male Wistar rat pups on postnatal days 5 − 18, once daily. Upon completion of behavioral testing at the age of three months, some of the animals in the diprotin A-treated (n = 8), sitagliptin-treated (n = 7), and control (saline-treated rats, n = 8) groups were decapitated and the brain structures were immediately frozen in liquid nitrogen for subsequent analysis of gene expression. Quantitative Real-Time-PCR (qRT-PCR) was performed using TaqMan probes and ready-to-use qPCRmix-HS SYBR mixture. Data were normalized to GAPDH mRNA expression and calculated as relative fold changes compared to control rats using method 2–DDCt. Differences in gene expression levels between experimental and control groups were assessed using Kruskal–Wallis ANOVA followed by a multiple comparisons analysis of the mean ranks. Results: In the sitagliptin-treated rats, the levels of DPP4 and SERT mRNA were increased more than twice in the striatum (p = 0.010 and p = 0.034 vs. the controls, respectively) with a trend to increase the expression of genes encoding MAOA and MAOB. Increased expression of MAOA gene was shown in the amygdala (p = 0.023 vs. the diprotin A-treated group). In the diprotin A-treated rats, we observed the increase of gene PREP
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mRNA expression in the striatum (p = 0.022 vs. the controls) and the decrease of gene MAOB mRNA expression in the amygdala (p = 0.012 vs. the sitagliptin-treated group). The data revealed a tendency to a down-regulation of gene expression of SERT in the frontal cortex and amygdala and an increase in gene expression of MAOA in the hypothalamus. Conclusion: The changes in gene expression in the brain of the adult rats treated with DPP4 inhibitors in the early postnatal period are associated with behavioral alterations and may be responsible for their development. Data suggest that different gene-expression patterns in the sitagliptin- and diprotin A-treated rats are most likely the result of epigenetic regulation when a long-acting DPP4 inhibitor is administered in the neonatal period. References [1] Cerd´a, M., Sagdeo, A., Johnson, J., Galea, S., 2010. Genetic and environmental influences on psychiatric comorbidity, A systematic review. J Affect Disord 126(1−2), 14−38. [2] Lesch, K.P., Araragi, N., Waider, J., van den Hove, D., Gutknecht, L., 2012. Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci 367(1601), 2426–2443. [3] Maes, M., Bonaccorso, S. 2004. Lower activities of serum peptidases predict higher depressive and anxiety levels following interferon-alphabased immunotherapy in patients with hepatitis C. Acta Psychiatr Scand 109(2), 126–131. [4] Krupina, N.A., Khlebnikova, N.N., 2016. Neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin induces depression-like behavior, anxiety, and latent aggression in adolescent and adult rats. J Behav Brain Sci 6(4), in press. Disclosure statement: These studies were supported by RFBR (grant number: 15−04–08784)
P.1.a.019 DRD2 gene polymorphisms association with severity of depressive symptoms and antidepressive therapy response in patients with depressive disorders I. Losenkov1 ° , I.V. Pozhidaev1 , D.Z. Osmanova1 , G.G. Simutkin2 Health Research Institute, Laboratory of molecular genetics and biochemistry, Tomsk, Russia; 2 Mental Health Research Institute, Department of affective disorders, Tomsk, Russia
1 Mental
Depression is considered to be important social, economical and medical problem of modern society [1]. Nowadays its considered that dysfunction of dopaminergic system can be one of the depression pathogenesis factors. Deficiency of dopamine signalization is responsible for several depressive symptoms such as cognitive deficit, lack of motivation, anhedonia, reduction of motor activity, growing appetite [2]. That is why searching of association of genes of dopaminergic system is very important. Purpose of the study: The aim of the research was investigation of association of single nucleotide polymorphisms (SNP) of DRD2 gene, encoding dopamine receptor D2, with severity of depressive symptoms and antidepressive therapy response in patients with depressive disorders. Materials and Methods: 161 patients (90 patients with depressive episode (ICD-10: F32), 71 patients with recurrent depressive disorder (ICD-10: F33)) were included in the study. Severity of depressive symptoms on the baseline and on the 14th and 28th day of therapy was evaluated using Hamilton scale (HDRS-17) and Clinical Global Impression − Severity scale
P.1.a.018 Gene expression in the brain of adult rats with behavioural alterations caused by neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin N.A. Krupina1 ° , E.A. Zubkov2 , E.V. Orshanskaya3 , Y.A. Zorkina2 , N.N. Khlebnikova1 1 Institute of General Pathology and Pathophysiology, Laboratory of General Pathology of the Nervous System, Moscow, Russia; 2 V. P. Serbsky State Research Center for Social and Forensic Psychiatry, Department of Fundamental and Applied Neurobiology, Moscow, Russia; 3 Institute of General Pathology and Pathophysiology, Department of General Pathology, Moscow, Russia Background: Depression, anxiety and aggressiveness represent a frequent long-term outcome of neurodevelopmental disorders. Clinical overlap of these disorders suppose that they share genetic risk factors [1,2]. Serine proteases dipeptidyl peptidase IV (DPP4, EC 3.4.14.5) and prolyl endopeptidase (PREP; EC 3.4.21.26) are involved in the pathophysiology of emotional and mood disorders [3]. Recently, we have revealed that adolescent and adult rats exhibit an increase in anxiety and depressionrelated behaviors with disinhibited aggression upon mild stress provocation after neonatal administration of two competitive, selective DPP4 inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg) [4]. Diprotin A exhibited a more significant negative impact on the animals’ behaviors compared to sitagliptin. These findings demonstrated the involvement of DPP4 in the genesis of emotional and motivational disorders. Objective: To study gene expression of DPP4, PREP, monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and serotonin transporter (SERT) in the brain structures of adult rats with emotional and motivational disorders induced by neonatal administration of DPP4 inhibitors sitagliptin and diprotin A. Methods: Sitagliptin (4 mg/kg) and diprotin A (2 mg/kg) were intraperitoneally administered to the male Wistar rat pups on postnatal days 5 − 18, once daily. Upon completion of behavioral testing at the age of three months, some of the animals in the diprotin A-treated (n = 8), sitagliptin-treated (n = 7), and control (saline-treated rats, n = 8) groups were decapitated and the brain structures were immediately frozen in liquid nitrogen for subsequent analysis of gene expression. Quantitative Real-Time-PCR (qRT-PCR) was performed using TaqMan probes and ready-to-use qPCRmix-HS SYBR mixture. Data were normalized to GAPDH mRNA expression and calculated as relative fold changes compared to control rats using method 2–DDCt. Differences in gene expression levels between experimental and control groups were assessed using Kruskal–Wallis ANOVA followed by a multiple comparisons analysis of the mean ranks. Results: In the sitagliptin-treated rats, the levels of DPP4 and SERT mRNA were increased more than twice in the striatum (p = 0.010 and p = 0.034 vs. the controls, respectively) with a trend to increase the expression of genes encoding MAOA and MAOB. Increased expression of MAOA gene was shown in the amygdala (p = 0.023 vs. the diprotin A-treated group). In the diprotin A-treated rats, we observed the increase of gene PREP
S173
mRNA expression in the striatum (p = 0.022 vs. the controls) and the decrease of gene MAOB mRNA expression in the amygdala (p = 0.012 vs. the sitagliptin-treated group). The data revealed a tendency to a down-regulation of gene expression of SERT in the frontal cortex and amygdala and an increase in gene expression of MAOA in the hypothalamus. Conclusion: The changes in gene expression in the brain of the adult rats treated with DPP4 inhibitors in the early postnatal period are associated with behavioral alterations and may be responsible for their development. Data suggest that different gene-expression patterns in the sitagliptin- and diprotin A-treated rats are most likely the result of epigenetic regulation when a long-acting DPP4 inhibitor is administered in the neonatal period. References [1] Cerd´a, M., Sagdeo, A., Johnson, J., Galea, S., 2010. Genetic and environmental influences on psychiatric comorbidity, A systematic review. J Affect Disord 126(1−2), 14−38. [2] Lesch, K.P., Araragi, N., Waider, J., van den Hove, D., Gutknecht, L., 2012. Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci 367(1601), 2426–2443. [3] Maes, M., Bonaccorso, S. 2004. Lower activities of serum peptidases predict higher depressive and anxiety levels following interferon-alphabased immunotherapy in patients with hepatitis C. Acta Psychiatr Scand 109(2), 126–131. [4] Krupina, N.A., Khlebnikova, N.N., 2016. Neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin induces depression-like behavior, anxiety, and latent aggression in adolescent and adult rats. J Behav Brain Sci 6(4), in press. Disclosure statement: These studies were supported by RFBR (grant number: 15−04–08784)
P.1.a.019 DRD2 gene polymorphisms association with severity of depressive symptoms and antidepressive therapy response in patients with depressive disorders I. Losenkov1 ° , I.V. Pozhidaev1 , D.Z. Osmanova1 , G.G. Simutkin2 Health Research Institute, Laboratory of molecular genetics and biochemistry, Tomsk, Russia; 2 Mental Health Research Institute, Department of affective disorders, Tomsk, Russia
1 Mental
Depression is considered to be important social, economical and medical problem of modern society [1]. Nowadays its considered that dysfunction of dopaminergic system can be one of the depression pathogenesis factors. Deficiency of dopamine signalization is responsible for several depressive symptoms such as cognitive deficit, lack of motivation, anhedonia, reduction of motor activity, growing appetite [2]. That is why searching of association of genes of dopaminergic system is very important. Purpose of the study: The aim of the research was investigation of association of single nucleotide polymorphisms (SNP) of DRD2 gene, encoding dopamine receptor D2, with severity of depressive symptoms and antidepressive therapy response in patients with depressive disorders. Materials and Methods: 161 patients (90 patients with depressive episode (ICD-10: F32), 71 patients with recurrent depressive disorder (ICD-10: F33)) were included in the study. Severity of depressive symptoms on the baseline and on the 14th and 28th day of therapy was evaluated using Hamilton scale (HDRS-17) and Clinical Global Impression − Severity scale