Esen Gumuslu

Effects of fluoxetine, tianeptine and olanzapine on unpredictable chronic mild stress-induced depression-like behavior in mice

AIMS Tianeptine is an atypical antidepressant drug that has a different mechanism of action than other antidepressants. Olanzapine is an atypical antipsychotic drug used for the treatment of schizophrenia. The present study was undertaken to investigate effects of chronic administration of tianeptine or olanzapine on unpredictable chronic mild stress (UCMS)-induced depression-like behavior in mice compared to a widely used SSRI antidepressant, fluoxetine. MAIN METHODS Male inbred BALB/c mice were subjected to different kinds of stressors several times a day for 7weeks and were treated intraperitoneally with tianeptine (5mg/kg), olanzapine (2.5mg/kg), fluoxetine (15mg/kg) or vehicle for 5weeks (n=7-8 per group). KEY FINDINGS All the drugs tested prevented stress-induced deficit in coat state during UCMS procedure, in grooming behavior in the splash test, decreased the attack frequency in the resident intruder test and decreased the immobility time in the tail suspension test. In the open field test olanzapine had anxiolytic-like effects in both stressed and non-stressed mice. Tianeptine, olanzapine and fluoxetine decreased the enhanced levels of plasma ACTH and IL-6. Chronic treatment with tianeptine resulted in a significant increase in both total number and density of BrdU-labeled cells in stressed animals, while fluoxetine and olanzapine had a partial effect. SIGNIFICANCE The results of this study support the hypothesis that tianeptine can be as effective as fluoxetine for the treatment of depression in spite of the differences in the mechanism of action of these drugs. Moreover, olanzapine could be used effectively in psychotic patients with depression.

The effects of tianeptine, olanzapine and fluoxetine on the cognitive behaviors of unpredictable chronic mild stress-exposed mice.

BACKGROUND Strong evidence indicates that impaired cognition is a core element of depression, and antidepressant treatment may ameliorate cognitive impairments experienced by depressive patients. Present study was performed to investigate effects of chronic tianeptine (5 mg/kg) or olanzapine (2.5 mg/kg) administration on cognitive behaviors of unpredictable chronic mild stress (UCMS)-exposed mice and to compare these effects to those induced by widely used SSRI antidepressant fluoxetine (15 mg/kg) in mice. METHODS To investigate effects of these drugs, the Morris water maze test (MWM), elevated plus maze test (EPM) and radial arm maze test (RAM) were used. The effects of stress and drugs on gene expression in the hippocampus was determined by quantitative Real Time-PCR. RESULTS In MWM test, fluoxetine significantly increased escape latency of non-stressed mice in acquisition sessions and decreased time spent in escape platform quadrant in probe trial; tianeptine and olanzapine decreased enhancement in escape latency, and only olanzapine significantly enhanced attenuation in time spent in the escape platform quadrant in UCMS-exposed mice. In EPM test, all drugs significantly decreased enhancement in transfer latency in UCMS-exposed mice. In RAM test, fluoxetine significantly increased number of errors made by both non-stressed and UCMS-exposed mice. CONCLUSION Quantitative real-time PCR revealed that CREB and BDNF gene expression levels were significantly decreased in UCMS-exposed group, and this effect was significantly reversed by each of drugs tested. Our results seem to be test dependent and should be further investigated using different learning and memory tasks.

The Antidepressant Agomelatine Improves Memory Deterioration and Upregulates CREB and BDNF Gene Expression Levels in Unpredictable Chronic Mild Stress (UCMS)-Exposed Mice

Agomelatine, a novel antidepressant with established clinical efficacy, acts as an agonist of melatonergic MT1 and MT2 receptors and as an antagonist of 5-HT2C receptors. The present study was undertaken to investigate whether chronic treatment with agomelatine would block unpredictable chronic mild stress (UCMS)-induced cognitive deterioration in mice in passive avoidance (PA), modified elevated plus maze (mEPM), novel object recognition (NOR), and Morris water maze (MWM) tests. Moreover, the effects of stress and agomelatine on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus was also determined using quantitative real-time polymerase chain reaction (RT-PCR). Male inbred BALB/c mice were treated with agomelatine (10 mg/kg, i.p.), melatonin (10 mg/kg), or vehicle daily for five weeks. The results of this study revealed that UCMS-exposed animals exhibited memory deterioration in the PA, mEPM, NOR, and MWM tests. The chronic administration of melatonin had a positive effect in the PA and +mEPM tests, whereas agomelatine had a partial effect. Both agomelatine and melatonin blocked stress-induced impairment in visual memory in the NOR test and reversed spatial learning and memory impairment in the stressed group in the MWM test. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in UCMS-exposed mice, and these alterations were reversed by chronic agomelatine or melatonin treatment. Thus, agomelatine plays an important role in blocking stress-induced hippocampal memory deterioration and activates molecular mechanisms of memory storage in response to a learning experience.

Exenatide enhances cognitive performance and upregulates neurotrophic factor gene expression levels in diabetic mice

Exenatide is a potent and selective agonist for the GLP‐1 (glucagon‐like peptide‐1) receptor. Recent studies are focused on the effects of GLP‐1 analogues on hippocampal neurogenesis, cognition, learning and memory functions. The aim of this study was to assess the effects of chronic exenatide treatment (0.1 μg/kg, s.c, twice daily for 2 weeks) on spatial memory functions by using the modified elevated plus maze (mEPM) test and emotional memory functions by using the passive avoidance (PA) test in streptozotocin/nicotinamide (STZ‐NA)‐induced diabetic mice. As the genes involved in neurite remodelling are among the primary targets of regulation, the effects of diabetes and chronic administration of exenatide on brain‐derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus of mice were also determined using quantitative real‐time polymerase chain reaction (RT‐PCR). This study revealed that in the mEPM and PA tests, type‐2 diabetes‐induced mice exhibited significant impairment of learning and memory which were ameliorated by GLP‐1 receptor agonist exenatide. Quantitative RT‐PCR revealed that CREB and BDNF gene expression levels were downregulated in diabetic mice, and these alterations were increased by exenatide treatment. Since, exenatide improves cognitive ability in STZ/NA‐induced diabetic mice and activates molecular mechanisms of memory storage in response to a learning experience, it may be a candidate for alleviation of mood and cognitive disorder.

Effects of chronic administration of adipokinetic and hypertrehalosemic hormone on animal behavior, BDNF, and CREB expression in the hippocampus and neurogenesis in mice

Neurosecretory cells in corpus cardiacum of insects synthesize a set of hormones that are called adipokinetic, hypertrehalosaemic or hyperprolinaemic, depending on insect in question. This study investigated effects of chronic administration of Anax imperator adipokinetic hormone (Ani‐AKH), Libellula auripennis adipokinetic hormone (Lia‐AKH), and Phormia‐Terra hypertrehalosaemic hormone (Pht‐HrTH) on depression, anxiety, analgesy, locomotion in forced swimming (FST), elevated plus‐maze (EPM), hot plate, and locomotor activity tests. Ani‐AKH (1 and 2 mg/kg), Lia‐AKH (1 and 2 mg/kg), and Pht‐HrTH (1 and 2 mg/kg) had antidepressant effects in forced swimming test. Lia‐AKH (2 mg/kg) and Pht‐HrTH (1 and 2 mg/kg) had anxiolytic effects when given chronically in elevated plus‐maze test. Ani‐AKH (1 and 2 mg/kg) and Pht‐HrTH (2 mg/kg) had antinociceptive effects in hot plate test in male balb‐c mice. Ani‐AKH (2 mg/kg), Lia‐AKH (1 and 2 mg/kg), and Pht‐HrTH had locomotion‐enhancing effects in locomotor activity test in male balb‐c mice. Drug treatment significantly increased brain‐derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) gene expression levels compared to control levels. Pht‐HrTH and Ani‐AKH groups had significantly increased numbers of BrdU‐labeled cells, while neurodegeneration was lower in the Pht‐HrTH group. Our study showed that AKH/RPCH family peptides may be used in treatment of psychiatric illness such as depression and anxiety, in treatment of pain and in diseases related to locomotion system. AKH/RPCH family peptides increase neurotrophic factors in brain and have potential proliferative and neuroprotective effects in hippocampal neurogenesis and neurodegeneration.

Exenatide Alters Gene Expression of Neural Cell Adhesion Molecule (NCAM), Intercellular Cell Adhesion Molecule (ICAM), and Vascular Cell Adhesion Molecule (VCAM) in the Hippocampus of Type 2 Diabetic Model Mice.

Background Glucagon-like peptide-1 (GLP-1), a potent and selective agonist for the GLP-1 receptor, ameliorates the symptoms of diabetes through stimulation of insulin secretion. Exenatide is a potent and selective agonist for the GLP-1 receptor. Cell adhesion molecules are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. Material/Methods The present study demonstrated the effects of exenatide treatment (0.1 μg/kg, subcutaneously, twice daily for 2 weeks) on the gene expression levels of cell adhesion molecules, neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the brain tissue of diabetic BALB/c male mice by real-time quantitative polymerase chain reaction (PCR). Diabetes was induced by streptozotocin/nicotinamide (STZ-NA) injection to male mice. Results The results of this study revealed that hippocampal gene expression of NCAM, ICAM, and VCAM were found to be up-regulated in STZ-NA-induced diabetic mice compared to those of controls. A significant decrease in the gene expression levels of NCAM, ICAM, and VCAM were determined after 2 weeks of exenatide administration. Conclusions Cell adhesion molecules may be involved in the molecular mechanism of diabetes. Exenatide has a strong beneficial action in managing diabetes induced by STZ/NA by altering gene expression of NCAM, ICAM, and VCAM.

Gene-Expression Profiles in Generalized Aggressive Periodontitis: A Gene Network-Based Microarray Analysis

BACKGROUND In this study, molecular biomarkers that play a role in the development of generalized aggressive periodontitis (GAgP) are investigated using gingival tissue samples through omics-based whole-genome transcriptomics while using healthy individuals as background controls. METHODS Gingival tissue biopsies from 23 patients with GAgP and 25 healthy individuals were analyzed using gene-expression microarrays with network and pathway analyses to identify gene-expression patterns. To substantiate the results of the microarray studies, real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to assess the messenger RNA (mRNA) expression of MZB1 and DSC1. The microarrays and qRT-PCR resulted in similar gene-expression changes, confirming the reliability of the microarray results at the mRNA level. RESULTS As a result of the gene-expression microarray studies, four significant gene networks were identified. The most upregulated genes were found as MZB1, TNFRSF17, PNOC, FCRL5, LAX1, BMS1P20, IGLL5, MMP7, SPAG4, and MEI1; the most downregulated genes were found as LOR, LAMB4, AADACL2, MAPT, ARG1, NPR3, AADAC, DSC1, LRRC4, and CHP2. CONCLUSIONS Functions of the identified genes that were involved in gene networks were cellular development, cell growth and proliferation, cellular movement, cell-cell signaling and interaction, humoral immune response, protein synthesis, cell death and survival, cell population and organization, organismal injury and abnormalities, molecular transport, and small-molecule biochemistry. The data suggest new networks that have important functions as humoral immune response and organismal injury/abnormalities. Future analyses may facilitate proteomic profiling analyses to identify gene-expression patterns related to clinical outcome.

Antidepressant-Like Activity of Agomelatine in the Mouse Unpredictable Chronic Mild Stress Model: Agomelatine has Antidepressant Effects in Mice

Preclinical Research

Exenatide upregulates gene expression of glucagon like peptide-1 receptor and nerve growth factor in streptozotocin/nicotinamide-induced diabetic mice

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that has modulating effects on insulin release. GLP‐1 and receptors for GLP‐1 are widely expressed throughout the body including the brain. The expression of GLP‐1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP‐1 receptor stimulation enhances glucose‐dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose‐derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimers disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP‐1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP‐1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 μg/kg, s.c., twice daily for 2 weeks) on GLP‐1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ–NA)‐induced diabetic mice were assessed by quantitative real‐time polymerase chain reaction (RT‐PCR). The results of this study revealed that hippocampal gene expression of GLP‐1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP‐1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP‐1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA‐induced diabetes.

PM434. Haloperidol exerts depression-like behaviour in the forced swimming test while it has anxiolytic-like and analgesic effects in the elevated plus maze and hot plate tests: Altered gen expression levels of FGF2, synapsin and NGF in the hippocampus of mice.

Depression and anxiety is frequently seen in many schizophrenic patients and may be further aggravated or diminished by antipsychotic treatments. Haloperidol is a conventional antipsychotic used in schizophrenia and psychosis. Neutrophins are a family of structurally related proteins regulating the survival,differentiation, and maintance of function of different neuron populations. Fibroblast growth factor-2 (FGF2) has an important role in many aspects of CNS functioning. Synapsin, another key marker of synaptic activity plays an important role in hippocampally based behaviors. There is evidence that nevre growth factor (NGF) also mediates multiple biological phenomena. We aimed to investigate the effects of haloperidol on depression, anxiety and pain in naive mice, using forced swiming (FST), elevated plus maze (EPM) and hot plate tests. Since genes involved in neurite remodeling are among the primary targets of regulation, effects of haloperidol on expression levels of FGF2, synapsin and NGF in the hippocampus of mice were determined using quantitative RT-PCR. Mice were treated chronically with haloperidol (0.125 and 0.25 mg/kg;15 days, n=10/per group) and haloperidol was also administered intraperitoneally 60 min before the tests. Fluoxetine, diazepam or metamizol-sodium were used as reference drugs. The results of this study revealed that: (1) In the FST, fluoxetine significantly decreased immobility time (p<0.001) while haloperidol significantly increased (0.25 mg/kg, (p<0.05) this parameter. (2) In the EPM test, diazepam (p<0.001) and haloperidol (0.25 mg/kg) significantly increased % time spent in open arm’s and % open arm entries (p<0.001; p<0.01). (3) In the hot plate test, metamizol sodium (p<0.001) and haloperidol (0.125 mg/kg and 0.25 mg/kg, p<0.05, p<0.001 respectively) significantly increased the latency for licking the hindpaws. (4) Haloperidol significantly increased expression of FGF2 and synapsin while it decreased expression of NGF.Thus haloperidol exerts depression-,anxiolytic-like behaviour, analgesic effects and alters gen expression levels of FGF2, synapsin and NGF in mice. PM435 Targeting Functional Selectivity of the Dopamine D2 Receptor for Treatment of Schizophrenia-like Behaviors William Wetsel1, Marc G. Caron1, Jian Jin2, Su Mi Park1, Vladimir M. Pogorelov1, Ramona M. Rodriguiz1, Claire M. Schmerberg1 1Duke University Medical Center, USA, 2Icahn School of Medicine at