Sulev Kõks - Academia.edu (original) (raw)

Papers by Sulev Kõks

Research paper thumbnail of Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

Naunyn-Schmiedeberg's Archives of Pharmacology, 1995

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine ag... more We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 1 lth day was antagonized by haloperidol (0.05 and 0.1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1mg/kgi.p.) of rats, sensitized by

Research paper thumbnail of Pharmacological Comparison of Antipsychotic Drugs and σ-Antagonists in Rodents

Acta Pharmacologica Et Toxicologica, 1994

We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists... more We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists (remoxipride, cinuperone, alpha-(4-fluorophenyl)-4-(-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole) in the radio-ligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2-receptors in the striatum and their ability to block apomorphine-, amphetamine- and quipazine-induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1-5-HT2- and sigma receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2-receptors was following: haloperidol > chlorpromazine > or = clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine-induced aggressiveness and yawning, whereas at 5-HT2-receptors clozapine was more active than chlorpromazine. The weak activity of sigma antagonists at dopamine2 receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine-induced stereotypy and aggressiveness is not related to its activity at sigma receptors, because the other sigma antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2 receptors. In conclusion, the present study revealed only weak activity of sigma antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of sigma antagonists is doubtful.

Research paper thumbnail of Inhibition of nitric oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze

Neuroreport, 1995

The action of inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAM... more The action of inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME) (1-20 mg kg-1) on the exploratory behaviour of rats in the elevated plus-maze was studied. L-NAME induced an anxiolytic-like effect in the plus-maze test, showing a reverse U-shape action behaviour, with a maximal effect at 10 mg kg-1. This effect was not related to a non-specific increase in motor activity, since in the open field test L-NAME did not affect locomotor activity of rats. Pretreatment of rats with L-NAME (1-10 mg kg-1) also tended to attenuate the anti-exploratory action of CCK agonist caerulein (5 micrograms kg-1), but this action was not significant. In conclusion, it appears that NO may be involved in the process that can lead to anxiety in the rat.

Research paper thumbnail of P.3.05 Association and haplotype analaysis of90 single-nucleotide polymorphisms in mood disorders

European Neuropsychopharmacology, 2005

Research paper thumbnail of P.3.031 Association study of 90 candidategenetic polymorphisms in panic disorder: Positive findings with SNPs in serotonin, cholecystokinin and dopamine related genes

European Neuropsychopharmacology, 2004

Research paper thumbnail of Possible relations between the polymorphisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis

Research paper thumbnail of WITHDRAWN: TNF-Related Apoptosis-Inducing Ligand TRAIL as a Potential Biomarker for Early Pregnancy Complications

Journal of Clinical Endocrinology & Metabolism, 2012

Context: Recurrent miscarriage (RM) (at least three consecutive pregnancy losses) occurs in 1-3% ... more Context: Recurrent miscarriage (RM) (at least three consecutive pregnancy losses) occurs in 1-3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified.

Research paper thumbnail of Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage

Placenta, 2013

Maternal serum biomarker for early pregnancy failure a b s t r a c t Introduction: Recurrent misc... more Maternal serum biomarker for early pregnancy failure a b s t r a c t Introduction: Recurrent miscarriage (RM; !3 consecutive pregnancy losses) occurs in 1e3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified. We aimed to profile whole-genome differential gene expression in RM placental tissue, and to determine the protein levels of identified loci in maternal sera in early pregnancy. Methods: GeneChips (Affymetrix Ò ) were used for discovery and Taqman RT-qPCR assays for replication of mRNA expression in placentas from RM cases (n ¼ 13) compared to uncomplicated pregnancies matched for gestational age (n ¼ 23). Concentrations of soluble TRAIL (sTRAIL) and calprotectin in maternal serum in normal first trimester (n ¼ 35) and failed pregnancies (early miscarriage, n ¼ 18, late miscarriage, n ¼ 4; tubal pregnancy, n ¼ 11) were determined using ELISA. Results: In RM placentas 30 differentially expressed (with nominal P-value < 0.05) transcripts were identified. Significantly increased placental mRNA expression of TNF-related apoptosis-inducing ligand (TRAIL; P ¼ 1.4 Â 10 À3 ; fold-change 1.68) and S100A8 (P ¼ 7.9 Â 10 À4 ; fold-change 2.56) encoding for inflammatory marker calprotectin (S100A8/A9) was confirmed by RT-qPCR. When compared to normal first trimester pregnancy (sTRAIL 16.1 AE 1.6 pg/ml), significantly higher maternal serum concentration of sTRAIL was detected at the RM event (33.6 AE 4.3 pg/ml, P ¼ 0.00027), and in pregnant women, who developed an unpredicted miscarriage 2e50 days after prospective serum sampling (28.5 AE 4.4 pg/ml, P ¼ 0.039). Women with tubal pregnancy also exhibited elevated sTRAIL (30.5 AE 3.9 pg/ml, P ¼ 0.035). Maternal serum levels of calprotectin were neither diagnostic nor prognostic to early pregnancy failures (P > 0.05). Conclusions: The study indicated of sTRAIL as a potential predictive biomarker in maternal serum for early pregnancy complications.

Research paper thumbnail of Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta

Epigenetics, 2014

Given the possible critical importance of placental gene imprinting and random monoallelic expres... more Given the possible critical importance of placental gene imprinting and random monoallelic expression on fetal and infant health, most of those genes must be identified, in order to understand the risks that the baby might meet during pregnancy and after birth. Therefore, the aim of the current study was to introduce a workflow and tools for analyzing imprinted and random monoallelic gene expression in human placenta, by applying whole-transcriptome (WT) RNA sequencing of placental tissue and genotyping of coding DNA variants in family trios. Ten family trios, each with a healthy spontaneous single-term pregnancy, were recruited. Total RNA was extracted for WT analysis, providing the full sequence information for the placental transcriptome. Parental and child blood DNA genotypes were analyzed by exome SNP genotyping microarrays, mapping the inheritance and estimating the abundance of parental expressed alleles. Imprinted genes showed consistent expression from either parental allele, as demonstrated by the SNP content of sequenced transcripts, while monoallelically expressed genes had random activity of parental alleles. We revealed 4 novel possible imprinted genes (LGALS8, LGALS14, PAPPA2 and SPTLC3) and confirmed the imprinting of 4 genes (AIM1, PEG10, RHOBTB3 and ZFAT-AS1) in human placenta. The major finding was the identification of 4 genes (ABP1, BCLAF1, IFI30 and ZFAT) with random allelic bias, expressing one of the parental alleles preferentially. The main functions of the imprinted and monoallelically expressed genes included: i) mediating cellular apoptosis and tissue development; ii) regulating inflammation and immune system; iii) facilitating metabolic processes; and iv) regulating cell cycle.

Research paper thumbnail of Transcriptional landscape of psoriasis identifies the involvement of IL36 and IL36RN

BMC Genomics, 2015

Background: In present study we performed whole transcriptome analysis in plaque psoriasis patien... more Background: In present study we performed whole transcriptome analysis in plaque psoriasis patients and compared lesional skin with non-lesional skin and with the skin from healthy controls. We sequenced total RNA from 12 lesional (LP), 12 non-lesional (NLP) and from 12 normal (C) skin biopsies.

Research paper thumbnail of Expression of class II cytokine genes in children's skin

Acta dermato-venereologica, 2014

Immune regulation of the skin plays an important role in susceptibility and development of illnes... more Immune regulation of the skin plays an important role in susceptibility and development of illnesses. The aim of our study was to localise the interleukin (IL)-10 family of cytokines, in children's skin and to determine possible age-related differences in the expression level. The mRNA expression level of IL10, IL19, IL20, IL22, IL24, IL26, IL28B, IL29 and their receptors IL10RA, IL10RB, IL20RA, IL20RB, IL22RA1, IL22RA2, IL28RA was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time PCR (qRT-PCR). Immunohistochemistry was performed to confirm the qRT-PCR findings. We found age-related differences in the expression of IL10RB, IL20, IL20RA, IL22RA1, IL22RA2, IL26 and IL28RA genes. Cell type-dependent expression of IL10 family cytokines was apparent in the skin. In addition to previously known differences in systemic immunological response of adults and children, the present results reveal differences in immune profile of adul...

Research paper thumbnail of The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells

The expression pattern of several genes associated with different processes in melanocytes, inclu... more The expression pattern of several genes associated with different processes in melanocytes, including melanogenesis, is changed in vitiligo patients. We evaluated possible changes in the expression of interleukin (IL)-10 family cytokines (IL26, IL-28A, IL28B, IL29), their receptor subunits (IL20RB, IL22RA2, IL28RA), and genes potentially related to functioning of melanocytes (MDM1, IFNA1, IFNB1, IFNG, and ICAM1) in the case of vitiligo. We observed mRNA expression in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and controls&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and peripheral blood mononuclear cells using quantitative real-time polymerase chain reaction. The mRNA expression pattern of IL20RB, IL22RA2, IL-28A, IL28B, IL28RA, MDM1, IFNA1, IFNB1, IFNG, and ICAM1 changed in vitiligo skin and/or peripheral blood mononuclear cells (PBMC) compared with controls. All of these genes may potentially be involved in vitiligo pathogenesis through controlling or participating in different pathways that regulate survival/apoptosis, development and migration of melanocytes, and melanogenesis. This study presents additional support for our previous findings about the importance of IL-10 family cytokines in vitiligo, in particular the possible involvement of IL-22. Further studies should be considered.

Research paper thumbnail of Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2008

Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are... more Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC i...

Research paper thumbnail of The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells

Human Immunology, 2012

The expression pattern of several genes associated with different processes in melanocytes, inclu... more The expression pattern of several genes associated with different processes in melanocytes, including melanogenesis, is changed in vitiligo patients. We evaluated possible changes in the expression of interleukin (IL)-10 family cytokines (IL26, IL-28A, IL28B, IL29), their receptor subunits (IL20RB, IL22RA2, IL28RA), and genes potentially related to functioning of melanocytes (MDM1, IFNA1, IFNB1, IFNG, and ICAM1) in the case of vitiligo. We observed mRNA expression in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and controls&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and peripheral blood mononuclear cells using quantitative real-time polymerase chain reaction. The mRNA expression pattern of IL20RB, IL22RA2, IL-28A, IL28B, IL28RA, MDM1, IFNA1, IFNB1, IFNG, and ICAM1 changed in vitiligo skin and/or peripheral blood mononuclear cells (PBMC) compared with controls. All of these genes may potentially be involved in vitiligo pathogenesis through controlling or participating in different pathways that regulate survival/apoptosis, development and migration of melanocytes, and melanogenesis. This study presents additional support for our previous findings about the importance of IL-10 family cytokines in vitiligo, in particular the possible involvement of IL-22. Further studies should be considered.

Research paper thumbnail of Gene Expression Analysis of the Corticotrophin-releasing Hormone-proopiomelanocortin System in Psoriasis Skin Biopsies

Acta Dermato Venereologica, 2013

The corticotrophin-releasing hormone-proopiomelanocortin (CRH-POMC) system in the skin coordinate... more The corticotrophin-releasing hormone-proopiomelanocortin (CRH-POMC) system in the skin coordinates pigmentation and the immune response. The aim of this study was to evaluate the regulatory role of the neuroendocrine system in the pathogenesis of psoriasis. Using quantitative real-time-PCR, mRNA expression levels of 15 genes related to the CRH-POMC system were measured in punch biopsies from lesional and non-lesional skin of patients with psoriasis and from skin of healthy control subjects. Statistically significant up-regulation of POMC, CRH receptor type 1, melanin-concentrating hormone receptor (MCHR1) and melanocortin receptors 2, 3 and 4 mRNA expression in lesional and in non-lesional skin compared with healthy control samples were established. Tyrosinase (TYR), T(Y)RP-1 and ASIP genes were statistically significantly down-regulated in lesional and non-lesional skin of psoriasis samples compared with healthy subjects. The up-regulation of POMC, melanocortin receptors, CRH receptor type 1 and MCHR1 in the lesional and non-lesional skin of psoriasis patients supports the importance of the local CRH-POMC system in the pathogenesis of psoriasis.

Research paper thumbnail of Expression Profile of Genes Associated with the Dopamine Pathway in Vitiligo Skin Biopsies and Blood Sera

Dermatology, 2012

Background: Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level ... more Background: Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed. Methods: With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway (PAH, PCD, TH, DDC, DBH, PNMT, GPX1,

Research paper thumbnail of Expression Profile of Genes Associated with the Dopamine Pathway in Vitiligo Skin Biopsies and Blood Sera

Dermatology, 2012

Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level of dopamine ... more Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed. With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway (PAH, PCD, TH, DDC, DBH, PNMT, GPX1, MAOA, MAOB, COMT, DRD1-DRD5, VMAT1 and VMAT2) was observed in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and control subjects&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and blood. The mRNA expression of GPX1, DDC, MAOA, DRD1 and DRD5 differs in vitiligo skin and the protein level of DDC, MAOA, MAOB, DRD1 and DRD5 is changed in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and/or blood sera. The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway. We provide new data about changes of expression profile of the dopamine-synthesizing enzyme DDC, the dopamine-degrading enzymes MAOA and MAOB and the D1-like family dopamine receptors in vitiligo skin and blood sera.

Research paper thumbnail of Pharmacological Comparison of Antipsychotic Drugs and σ-Antagonists in Rodents

Pharmacology & Toxicology, 1994

We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists... more We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists (remoxipride, cinuperone, alpha-(4-fluorophenyl)-4-(-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole) in the radio-ligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2-receptors in the striatum and their ability to block apomorphine-, amphetamine- and quipazine-induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1-5-HT2- and sigma receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2-receptors was following: haloperidol &gt; chlorpromazine &gt; or = clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine-induced aggressiveness and yawning, whereas at 5-HT2-receptors clozapine was more active than chlorpromazine. The weak activity of sigma antagonists at dopamine2 receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine-induced stereotypy and aggressiveness is not related to its activity at sigma receptors, because the other sigma antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2 receptors. In conclusion, the present study revealed only weak activity of sigma antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of sigma antagonists is doubtful.

Research paper thumbnail of Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

Naunyn-Schmiedeberg's Archives of Pharmacology, 1995

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine ag... more We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 1 lth day was antagonized by haloperidol (0.05 and 0.1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1mg/kgi.p.) of rats, sensitized by

Research paper thumbnail of Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine ag... more We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 1 lth day was antagonized by haloperidol (0.05 and 0.1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1mg/kgi.p.) of rats, sensitized by

Research paper thumbnail of Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

Naunyn-Schmiedeberg's Archives of Pharmacology, 1995

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine ag... more We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 1 lth day was antagonized by haloperidol (0.05 and 0.1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1mg/kgi.p.) of rats, sensitized by

Research paper thumbnail of Pharmacological Comparison of Antipsychotic Drugs and σ-Antagonists in Rodents

Acta Pharmacologica Et Toxicologica, 1994

We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists... more We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists (remoxipride, cinuperone, alpha-(4-fluorophenyl)-4-(-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole) in the radio-ligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2-receptors in the striatum and their ability to block apomorphine-, amphetamine- and quipazine-induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1-5-HT2- and sigma receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2-receptors was following: haloperidol &gt; chlorpromazine &gt; or = clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine-induced aggressiveness and yawning, whereas at 5-HT2-receptors clozapine was more active than chlorpromazine. The weak activity of sigma antagonists at dopamine2 receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine-induced stereotypy and aggressiveness is not related to its activity at sigma receptors, because the other sigma antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2 receptors. In conclusion, the present study revealed only weak activity of sigma antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of sigma antagonists is doubtful.

Research paper thumbnail of Inhibition of nitric oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze

Neuroreport, 1995

The action of inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAM... more The action of inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME) (1-20 mg kg-1) on the exploratory behaviour of rats in the elevated plus-maze was studied. L-NAME induced an anxiolytic-like effect in the plus-maze test, showing a reverse U-shape action behaviour, with a maximal effect at 10 mg kg-1. This effect was not related to a non-specific increase in motor activity, since in the open field test L-NAME did not affect locomotor activity of rats. Pretreatment of rats with L-NAME (1-10 mg kg-1) also tended to attenuate the anti-exploratory action of CCK agonist caerulein (5 micrograms kg-1), but this action was not significant. In conclusion, it appears that NO may be involved in the process that can lead to anxiety in the rat.

Research paper thumbnail of P.3.05 Association and haplotype analaysis of90 single-nucleotide polymorphisms in mood disorders

European Neuropsychopharmacology, 2005

Research paper thumbnail of P.3.031 Association study of 90 candidategenetic polymorphisms in panic disorder: Positive findings with SNPs in serotonin, cholecystokinin and dopamine related genes

European Neuropsychopharmacology, 2004

Research paper thumbnail of Possible relations between the polymorphisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis

Research paper thumbnail of WITHDRAWN: TNF-Related Apoptosis-Inducing Ligand TRAIL as a Potential Biomarker for Early Pregnancy Complications

Journal of Clinical Endocrinology & Metabolism, 2012

Context: Recurrent miscarriage (RM) (at least three consecutive pregnancy losses) occurs in 1-3% ... more Context: Recurrent miscarriage (RM) (at least three consecutive pregnancy losses) occurs in 1-3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified.

Research paper thumbnail of Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage

Placenta, 2013

Maternal serum biomarker for early pregnancy failure a b s t r a c t Introduction: Recurrent misc... more Maternal serum biomarker for early pregnancy failure a b s t r a c t Introduction: Recurrent miscarriage (RM; !3 consecutive pregnancy losses) occurs in 1e3% of fertile couples. No biomarkers with high predictive value of threatening miscarriage have been identified. We aimed to profile whole-genome differential gene expression in RM placental tissue, and to determine the protein levels of identified loci in maternal sera in early pregnancy. Methods: GeneChips (Affymetrix Ò ) were used for discovery and Taqman RT-qPCR assays for replication of mRNA expression in placentas from RM cases (n ¼ 13) compared to uncomplicated pregnancies matched for gestational age (n ¼ 23). Concentrations of soluble TRAIL (sTRAIL) and calprotectin in maternal serum in normal first trimester (n ¼ 35) and failed pregnancies (early miscarriage, n ¼ 18, late miscarriage, n ¼ 4; tubal pregnancy, n ¼ 11) were determined using ELISA. Results: In RM placentas 30 differentially expressed (with nominal P-value < 0.05) transcripts were identified. Significantly increased placental mRNA expression of TNF-related apoptosis-inducing ligand (TRAIL; P ¼ 1.4 Â 10 À3 ; fold-change 1.68) and S100A8 (P ¼ 7.9 Â 10 À4 ; fold-change 2.56) encoding for inflammatory marker calprotectin (S100A8/A9) was confirmed by RT-qPCR. When compared to normal first trimester pregnancy (sTRAIL 16.1 AE 1.6 pg/ml), significantly higher maternal serum concentration of sTRAIL was detected at the RM event (33.6 AE 4.3 pg/ml, P ¼ 0.00027), and in pregnant women, who developed an unpredicted miscarriage 2e50 days after prospective serum sampling (28.5 AE 4.4 pg/ml, P ¼ 0.039). Women with tubal pregnancy also exhibited elevated sTRAIL (30.5 AE 3.9 pg/ml, P ¼ 0.035). Maternal serum levels of calprotectin were neither diagnostic nor prognostic to early pregnancy failures (P > 0.05). Conclusions: The study indicated of sTRAIL as a potential predictive biomarker in maternal serum for early pregnancy complications.

Research paper thumbnail of Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta

Epigenetics, 2014

Given the possible critical importance of placental gene imprinting and random monoallelic expres... more Given the possible critical importance of placental gene imprinting and random monoallelic expression on fetal and infant health, most of those genes must be identified, in order to understand the risks that the baby might meet during pregnancy and after birth. Therefore, the aim of the current study was to introduce a workflow and tools for analyzing imprinted and random monoallelic gene expression in human placenta, by applying whole-transcriptome (WT) RNA sequencing of placental tissue and genotyping of coding DNA variants in family trios. Ten family trios, each with a healthy spontaneous single-term pregnancy, were recruited. Total RNA was extracted for WT analysis, providing the full sequence information for the placental transcriptome. Parental and child blood DNA genotypes were analyzed by exome SNP genotyping microarrays, mapping the inheritance and estimating the abundance of parental expressed alleles. Imprinted genes showed consistent expression from either parental allele, as demonstrated by the SNP content of sequenced transcripts, while monoallelically expressed genes had random activity of parental alleles. We revealed 4 novel possible imprinted genes (LGALS8, LGALS14, PAPPA2 and SPTLC3) and confirmed the imprinting of 4 genes (AIM1, PEG10, RHOBTB3 and ZFAT-AS1) in human placenta. The major finding was the identification of 4 genes (ABP1, BCLAF1, IFI30 and ZFAT) with random allelic bias, expressing one of the parental alleles preferentially. The main functions of the imprinted and monoallelically expressed genes included: i) mediating cellular apoptosis and tissue development; ii) regulating inflammation and immune system; iii) facilitating metabolic processes; and iv) regulating cell cycle.

Research paper thumbnail of Transcriptional landscape of psoriasis identifies the involvement of IL36 and IL36RN

BMC Genomics, 2015

Background: In present study we performed whole transcriptome analysis in plaque psoriasis patien... more Background: In present study we performed whole transcriptome analysis in plaque psoriasis patients and compared lesional skin with non-lesional skin and with the skin from healthy controls. We sequenced total RNA from 12 lesional (LP), 12 non-lesional (NLP) and from 12 normal (C) skin biopsies.

Research paper thumbnail of Expression of class II cytokine genes in children's skin

Acta dermato-venereologica, 2014

Immune regulation of the skin plays an important role in susceptibility and development of illnes... more Immune regulation of the skin plays an important role in susceptibility and development of illnesses. The aim of our study was to localise the interleukin (IL)-10 family of cytokines, in children's skin and to determine possible age-related differences in the expression level. The mRNA expression level of IL10, IL19, IL20, IL22, IL24, IL26, IL28B, IL29 and their receptors IL10RA, IL10RB, IL20RA, IL20RB, IL22RA1, IL22RA2, IL28RA was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time PCR (qRT-PCR). Immunohistochemistry was performed to confirm the qRT-PCR findings. We found age-related differences in the expression of IL10RB, IL20, IL20RA, IL22RA1, IL22RA2, IL26 and IL28RA genes. Cell type-dependent expression of IL10 family cytokines was apparent in the skin. In addition to previously known differences in systemic immunological response of adults and children, the present results reveal differences in immune profile of adul...

Research paper thumbnail of The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells

The expression pattern of several genes associated with different processes in melanocytes, inclu... more The expression pattern of several genes associated with different processes in melanocytes, including melanogenesis, is changed in vitiligo patients. We evaluated possible changes in the expression of interleukin (IL)-10 family cytokines (IL26, IL-28A, IL28B, IL29), their receptor subunits (IL20RB, IL22RA2, IL28RA), and genes potentially related to functioning of melanocytes (MDM1, IFNA1, IFNB1, IFNG, and ICAM1) in the case of vitiligo. We observed mRNA expression in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and controls&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and peripheral blood mononuclear cells using quantitative real-time polymerase chain reaction. The mRNA expression pattern of IL20RB, IL22RA2, IL-28A, IL28B, IL28RA, MDM1, IFNA1, IFNB1, IFNG, and ICAM1 changed in vitiligo skin and/or peripheral blood mononuclear cells (PBMC) compared with controls. All of these genes may potentially be involved in vitiligo pathogenesis through controlling or participating in different pathways that regulate survival/apoptosis, development and migration of melanocytes, and melanogenesis. This study presents additional support for our previous findings about the importance of IL-10 family cytokines in vitiligo, in particular the possible involvement of IL-22. Further studies should be considered.

Research paper thumbnail of Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2008

Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are... more Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC i...

Research paper thumbnail of The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells

Human Immunology, 2012

The expression pattern of several genes associated with different processes in melanocytes, inclu... more The expression pattern of several genes associated with different processes in melanocytes, including melanogenesis, is changed in vitiligo patients. We evaluated possible changes in the expression of interleukin (IL)-10 family cytokines (IL26, IL-28A, IL28B, IL29), their receptor subunits (IL20RB, IL22RA2, IL28RA), and genes potentially related to functioning of melanocytes (MDM1, IFNA1, IFNB1, IFNG, and ICAM1) in the case of vitiligo. We observed mRNA expression in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and controls&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and peripheral blood mononuclear cells using quantitative real-time polymerase chain reaction. The mRNA expression pattern of IL20RB, IL22RA2, IL-28A, IL28B, IL28RA, MDM1, IFNA1, IFNB1, IFNG, and ICAM1 changed in vitiligo skin and/or peripheral blood mononuclear cells (PBMC) compared with controls. All of these genes may potentially be involved in vitiligo pathogenesis through controlling or participating in different pathways that regulate survival/apoptosis, development and migration of melanocytes, and melanogenesis. This study presents additional support for our previous findings about the importance of IL-10 family cytokines in vitiligo, in particular the possible involvement of IL-22. Further studies should be considered.

Research paper thumbnail of Gene Expression Analysis of the Corticotrophin-releasing Hormone-proopiomelanocortin System in Psoriasis Skin Biopsies

Acta Dermato Venereologica, 2013

The corticotrophin-releasing hormone-proopiomelanocortin (CRH-POMC) system in the skin coordinate... more The corticotrophin-releasing hormone-proopiomelanocortin (CRH-POMC) system in the skin coordinates pigmentation and the immune response. The aim of this study was to evaluate the regulatory role of the neuroendocrine system in the pathogenesis of psoriasis. Using quantitative real-time-PCR, mRNA expression levels of 15 genes related to the CRH-POMC system were measured in punch biopsies from lesional and non-lesional skin of patients with psoriasis and from skin of healthy control subjects. Statistically significant up-regulation of POMC, CRH receptor type 1, melanin-concentrating hormone receptor (MCHR1) and melanocortin receptors 2, 3 and 4 mRNA expression in lesional and in non-lesional skin compared with healthy control samples were established. Tyrosinase (TYR), T(Y)RP-1 and ASIP genes were statistically significantly down-regulated in lesional and non-lesional skin of psoriasis samples compared with healthy subjects. The up-regulation of POMC, melanocortin receptors, CRH receptor type 1 and MCHR1 in the lesional and non-lesional skin of psoriasis patients supports the importance of the local CRH-POMC system in the pathogenesis of psoriasis.

Research paper thumbnail of Expression Profile of Genes Associated with the Dopamine Pathway in Vitiligo Skin Biopsies and Blood Sera

Dermatology, 2012

Background: Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level ... more Background: Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed. Methods: With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway (PAH, PCD, TH, DDC, DBH, PNMT, GPX1,

Research paper thumbnail of Expression Profile of Genes Associated with the Dopamine Pathway in Vitiligo Skin Biopsies and Blood Sera

Dermatology, 2012

Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level of dopamine ... more Dopamine has been proven to be toxic for melanocytes. In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed. With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway (PAH, PCD, TH, DDC, DBH, PNMT, GPX1, MAOA, MAOB, COMT, DRD1-DRD5, VMAT1 and VMAT2) was observed in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; and control subjects&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and blood. The mRNA expression of GPX1, DDC, MAOA, DRD1 and DRD5 differs in vitiligo skin and the protein level of DDC, MAOA, MAOB, DRD1 and DRD5 is changed in vitiligo patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; skin and/or blood sera. The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway. We provide new data about changes of expression profile of the dopamine-synthesizing enzyme DDC, the dopamine-degrading enzymes MAOA and MAOB and the D1-like family dopamine receptors in vitiligo skin and blood sera.

Research paper thumbnail of Pharmacological Comparison of Antipsychotic Drugs and σ-Antagonists in Rodents

Pharmacology & Toxicology, 1994

We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists... more We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and sigma antagonists (remoxipride, cinuperone, alpha-(4-fluorophenyl)-4-(-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY 14802) and rimcazole) in the radio-ligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2-receptors in the striatum and their ability to block apomorphine-, amphetamine- and quipazine-induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1-5-HT2- and sigma receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2-receptors was following: haloperidol &gt; chlorpromazine &gt; or = clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine-induced aggressiveness and yawning, whereas at 5-HT2-receptors clozapine was more active than chlorpromazine. The weak activity of sigma antagonists at dopamine2 receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine-induced stereotypy and aggressiveness is not related to its activity at sigma receptors, because the other sigma antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2 receptors. In conclusion, the present study revealed only weak activity of sigma antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of sigma antagonists is doubtful.

Research paper thumbnail of Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

Naunyn-Schmiedeberg's Archives of Pharmacology, 1995

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine ag... more We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 1 lth day was antagonized by haloperidol (0.05 and 0.1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1mg/kgi.p.) of rats, sensitized by

Research paper thumbnail of Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine ag... more We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 1 lth day was antagonized by haloperidol (0.05 and 0.1 mg/kgi.p.) and clozapine (10 mg/kgi.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kgi.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1mg/kgi.p.) of rats, sensitized by