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The role of zinc and GPR39 zinc receptor in depression
P.2.e. Mood disorders and treatment − Treatment (basic) of IL-1b precursor and mature protein levels, fluoxetine-treated subjects showing a decrease in pro-IL-1b (p = 0.0281, t = −2.368) and an increase in mature IL-1b (p = 0.0460, t = 2.135) compared to vehicle. IFN-g expression levels were modified by fluoxetine as compared to vehicle only in the stressful condition, treated mice showing decreased mRNA levels compared to controls (p = 0.0109, t = −3.007). RT-PCR analysis revealed that in microglia fluoxetine treatment administered in the enriched condition increased pro-inflammatory and decreased anti-inflammatory-related genes expression, in particular, iNOS (p = 0.041, t = −2.965), cd86 (p < 0.001, t = −6.399), IL-15 (p = 0.008, t = −3.925), IL-1b (p = 0.038, t = −2.675) and IL-23 (p < 0.001, t = −7.343) mRNA levels were increased, while arg-1 (p = 0.022, t = −3.059), ym-1 (p = 0.005, t = −5.547), IL-10 (p = 0.002, t = −5.201), IL-1ra (p = 0.025, t = −3.151) were reduced compared to vehicle. An opposite effect was found when fluoxetine treatment was administered in the stressful condition, specifically: Arg-1 (p = 0.007, t = −4.042), cd206 (p = 0.032, t = −2.783), ym-1 (p = 0.042, t = −2.961), TGF-b (p = 0.040, t = −2.605), socs3 (p = 0.031, t = −2.963), IL-10 (p = 0.006, t = −4.117), IL-1ra (p = 0.009, t = −3.752), fizz-1 (p = 0.022, t = −3.051) mRNA levels were increased, while iNOS (p = 0.005, t = −5.535), TNF-a (p = 0.018, t = −3.217), IL-1b (p = 0.008, t = −3.917), IL-6 (p = 0.026, t = −2.934) and IL-23 (p = 0.015, t = −3.366) levels were decreased compared to vehicle. Conclusions: The present findings show that the effects of SSRIs on inflammation depend on the quality of the environment and provide a possible explanation for the inter-individual differences in SSRI action and effects. The increased understanding of the molecular mechanisms underlying this interplay may allow for more effective personalization of antidepressant treatment strategies based on the quality of the living environment of the depressed patient. References [1] Carvalho, L.A., Torre, J.P., Papadopoulos, A.S., Poon, L., Juruena, M.F., Markopoulou, K., Cleare, A.J., Pariante, C.M., 2013. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. Journal of affective disorders 148, 136–140. [2] Horowitz, M.A., Wertz, J., Zhu, D., Cattaneo, A., Musaelyan, K., Nikkheslat, N., Thuret, S., Pariante, C.M., Zunszain, P.A., 2014 Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. Int J Neuropsychopharmacol. Oct 31, 18(3). [3] Branchi, I., Santarelli, S., Capoccia, S., Poggini, S., D’Andrea, I., Cirulli, F., Alleva, E., 2013. Antidepressant treatment outcome depends on the quality of the living environment: a pre-clinical investigation in mice. PLoS One 8, e62226.
P.2.e.013 The role of zinc and GPR39 zinc receptor in depression G. Starowicz1 ° , M. Jarosz1 , E. Fra˛ckiewicz1 , K. Młyniec1 1 Jagiellonian University Medical College, Department of Pharmacobiology, Krak´ow, Poland Introduction: Depression is a common psychiatric disorder that affects millions of people all over the world. It is also considered as one of the main causes of premature mortality and disability. Due to unsatisfactory effectiveness of antidepressants and accompanying side effects a new antidepressant drugs are required. A link between zinc and depressive-like behavior was confirmed in experimental zinc-deficient animals [1]. In our previous studies we observed an increased depressive-like behavior with anxiety component in knockout mice lacking the GPR39 [2]. GPR39 zinc receptor is expressed in several brain regions including
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hippocampus, frontal cortex and amygdala [3]. A significantly decreased levels of GPR39 were observed in the hippocampus and frontal cortex of zinc-deficient animal model of depression and suicide victims [4]. Moreover, GPR39 was up-regulated in the frontal cortex following chronic antidepressant treatment in mice, which suggests the involvement of the GPR39 in antidepressant mechanism of action [5]. Objectives: In the present study we compared the antidepressant activity of the GPR39 agonist (TC-G 1008) and ZnCl2 with the activity of monoamine-based antidepressants as well as glutamate-based drug with comparable antidepressant activity, in the forced swim test in mice. Materials and Methods: All animals (CD-1 male mice) were housed with 12-hour day-night cycle, temperature 22±2ºC and humidity at 55±5% with free access to food and water. Animals received the following drugs in acute (1 day) or chronic (14 days) doses: TC-G 1008 (15 mg/kg), ZnCl2 (30 mg/kg), imipramine (30 mg/kg), MK-801 (0.25 mg/kg), reboxetine (10 mg/kg), bupropion (10 mg/kg). All drugs were dissolved in 1% Tween and administered intraperitoneally. Control mice were treated with 1% Tween. In the forced swim test (FST) mice were dropped individually into the glass cylinders filled with water (22−24 ºC). After 2 minutes of adaptation the total immobility time was measured during next 4-minute test. Locomotor activity (overall distance travelled) was performed 30 minutes following drug injection. Results: In this study we observed a significant decrease in immobility time in the FST following acute treatment with TC-G 1008 or ZnCl2. These results were compared to imipramine and MK-801 which were also active in the FST. We also observed a significant decrease of immobility time in the groups receiving chronically TC-G 1008 or ZnCl2. There were no changes in locomotor activity. Chronic administration of imipramine, reboxetine, MK-801 or bupropion showed similar results to TC-G 1008 and ZnCl2 in both the FST and the locomotor activity test. Only in the group receiving MK-801 in chronic doses an increased overall distance travelled was observed. Conclusions: Both acute and chronic administration of TC-G 1008 and ZnCl2 cause antidepressant-like effects comparable to monoamine- and glutamate-based drugs with antidepressant activity. GPR39 should be considered as a new target for depression treatment. References [1] Whittle, N., Lubec, G., Signewald, N., 2009. Zinc deficiency induces enhanced depression-like behaviour and altered limbic activation reversed by antidepressant treatment in mice. Amino Acids 36, 147–158. [2] Młyniec, K., Budziszewska, B., Holst, B., Ostachowicz, B., Nowak, G., 2015. GPR39 (Zinc Receptor) Knockout Mice Exhibit Depression-Like Behavior and CREB/BDNF Down-Regulation in the Hippocampus. Int. J. Neuropsychopharmacol. 39, 1−8. [3] Besser, L., Chorin, E., Sekler, I., Silverman, W., F., Atkin, S., Russel, J., Hershfinkel M., 2012. Synaptically-Released Zinc Triggers Metabotropic Signaling via a Zinc Sensing Receptor in the Hippocampus. J Neurosci. 29, 997–1003. [4] Młyniec, K., Doboszewska, U., Szewczyk, B., Sowa-Ku´cma, M., Misztak, P., Piekoszewski, W., Trela, F., Ostachowicz, B., Nowak, G., 2014. The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims. Neuropharmacology 79, 290–297. [5] Młyniec, K., Nowak, G., 2013. GPR39 up-regulation after selective antidepressants. Neurochem Int 62, 936–939. Disclosure statement: The studies were supported by a grant from the Polish Ministry of Science and Higher Education ‘Iuventus Plus’ programme for the period 17.03.2015–16.03.2017 (project number: 0314/IP1/2015/73)
P.2.e.013 The role of zinc and GPR39 zinc receptor in depression G. Starowicz1 ° , M. Jarosz1 , E. Fra˛ckiewicz1 , K. Młyniec1 1 Jagiellonian University Medical College, Department of Pharmacobiology, Krak´ow, Poland Introduction: Depression is a common psychiatric disorder that affects millions of people all over the world. It is also considered as one of the main causes of premature mortality and disability. Due to unsatisfactory effectiveness of antidepressants and accompanying side effects a new antidepressant drugs are required. A link between zinc and depressive-like behavior was confirmed in experimental zinc-deficient animals [1]. In our previous studies we observed an increased depressive-like behavior with anxiety component in knockout mice lacking the GPR39 [2]. GPR39 zinc receptor is expressed in several brain regions including
S453
hippocampus, frontal cortex and amygdala [3]. A significantly decreased levels of GPR39 were observed in the hippocampus and frontal cortex of zinc-deficient animal model of depression and suicide victims [4]. Moreover, GPR39 was up-regulated in the frontal cortex following chronic antidepressant treatment in mice, which suggests the involvement of the GPR39 in antidepressant mechanism of action [5]. Objectives: In the present study we compared the antidepressant activity of the GPR39 agonist (TC-G 1008) and ZnCl2 with the activity of monoamine-based antidepressants as well as glutamate-based drug with comparable antidepressant activity, in the forced swim test in mice. Materials and Methods: All animals (CD-1 male mice) were housed with 12-hour day-night cycle, temperature 22±2ºC and humidity at 55±5% with free access to food and water. Animals received the following drugs in acute (1 day) or chronic (14 days) doses: TC-G 1008 (15 mg/kg), ZnCl2 (30 mg/kg), imipramine (30 mg/kg), MK-801 (0.25 mg/kg), reboxetine (10 mg/kg), bupropion (10 mg/kg). All drugs were dissolved in 1% Tween and administered intraperitoneally. Control mice were treated with 1% Tween. In the forced swim test (FST) mice were dropped individually into the glass cylinders filled with water (22−24 ºC). After 2 minutes of adaptation the total immobility time was measured during next 4-minute test. Locomotor activity (overall distance travelled) was performed 30 minutes following drug injection. Results: In this study we observed a significant decrease in immobility time in the FST following acute treatment with TC-G 1008 or ZnCl2. These results were compared to imipramine and MK-801 which were also active in the FST. We also observed a significant decrease of immobility time in the groups receiving chronically TC-G 1008 or ZnCl2. There were no changes in locomotor activity. Chronic administration of imipramine, reboxetine, MK-801 or bupropion showed similar results to TC-G 1008 and ZnCl2 in both the FST and the locomotor activity test. Only in the group receiving MK-801 in chronic doses an increased overall distance travelled was observed. Conclusions: Both acute and chronic administration of TC-G 1008 and ZnCl2 cause antidepressant-like effects comparable to monoamine- and glutamate-based drugs with antidepressant activity. GPR39 should be considered as a new target for depression treatment. References [1] Whittle, N., Lubec, G., Signewald, N., 2009. Zinc deficiency induces enhanced depression-like behaviour and altered limbic activation reversed by antidepressant treatment in mice. Amino Acids 36, 147–158. [2] Młyniec, K., Budziszewska, B., Holst, B., Ostachowicz, B., Nowak, G., 2015. GPR39 (Zinc Receptor) Knockout Mice Exhibit Depression-Like Behavior and CREB/BDNF Down-Regulation in the Hippocampus. Int. J. Neuropsychopharmacol. 39, 1−8. [3] Besser, L., Chorin, E., Sekler, I., Silverman, W., F., Atkin, S., Russel, J., Hershfinkel M., 2012. Synaptically-Released Zinc Triggers Metabotropic Signaling via a Zinc Sensing Receptor in the Hippocampus. J Neurosci. 29, 997–1003. [4] Młyniec, K., Doboszewska, U., Szewczyk, B., Sowa-Ku´cma, M., Misztak, P., Piekoszewski, W., Trela, F., Ostachowicz, B., Nowak, G., 2014. The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims. Neuropharmacology 79, 290–297. [5] Młyniec, K., Nowak, G., 2013. GPR39 up-regulation after selective antidepressants. Neurochem Int 62, 936–939. Disclosure statement: The studies were supported by a grant from the Polish Ministry of Science and Higher Education ‘Iuventus Plus’ programme for the period 17.03.2015–16.03.2017 (project number: 0314/IP1/2015/73)