Acute Stress Affects the Relaxin/Insulin-Like Family Peptide Receptor 3 mRNA Expression in Brain of Pubertal Male Wistar Rats.

The current literature suggests that relaxin-3/relaxin/insulin-like family peptide receptor 3 (RLN-3/RXFP-3) system is involved in the pathophysiology of affective disorders because the results of anatomical and pharmacological studies have shown that the RLN-3 signaling pathway plays a role in modulating the stress response, anxiety, arousal, depression-like behavior, and neuroendocrine homeostasis. The risk of developing mental illnesses in adulthood is increased by exposure to stress in early periods of life. The available data indicate that puberty is especially characterized by the development of the neural system and emotionality and is a "stress-sensitive" period. The presented study assessed the short-term changes in the expression of RLN-3 and RXFP-3 mRNA in the stress-dependent brain regions in male pubertal Wistar rats that had been subjected to acute stress. Three stressors were applied from 42 to 44 postnatal days (first day: a single forced swim; second day: stress on an elevated platform that was repeated three times; third day: restraint stress three times). Anxiety (open field, elevated plus maze test) and anhedonic-like behavior (sucrose preference test) were estimated during these tests. The corticosterone (CORT) levels and blood morphology were estimated. We found that the RXFP-3 mRNA expression decreased in the brainstem, whereas it increased in the hypothalamus 72 h after acute stress. These molecular changes were accompanied by the increased levels of CORT and anxiety-like behavior detected in the open field test that had been conducted earlier, that is, 24 h after the stress procedure. These findings shed new light on the neurochemical changes that are involved in the compensatory response to adverse events in pubertal male rats and support other data that suggest a regulatory interplay between the RLN-3 pathway and the hypothalamus-pituitary-adrenal axis activity in the mechanisms of anxiety-like behavior.

Glucose Influences the Response of Glioblastoma Cells to Temozolomide and Dexamethasone.

OBJECTIVE: Current research indicates that weakness of glucose metabolism plays an important role in silencing of invasiveness and growth of hypoxic tumors such as GBM. Moreover, there are indications that DXM, frequently used in treatment, may support GBM energy metabolism and provoke its recurrence. METHODS: We carried out in vitro experiments on the commercial T98G cell line and two primary GBM lines (HROG02, HROG17) treated with TMZ and/or DXM in physiological oxygen conditions for GBM (2.5% oxygen) and for comparison, in standard laboratory conditions (20% oxygen). The influence of different glucose levels on selected malignancy features of GBM cells-cellular viability and division, dynamic of cell culture changes, colony formation and concentration of InsR have been elevated. RESULTS: Under 2.5% oxygen and high glucose concentration, an attenuated cytotoxic effect of TMZ and intensification of malignancy features in all glioblastoma cell lines exposed to DXM was seen. Furthermore, preliminary retrospective analysis to assess the correlation between serum glucose levels and Ki-67 expression in surgical specimens derived from patients with GBM (IV) treated with radio-chemotherapy and prophylactic DXM therapy was performed. CONCLUSION: The data suggest a link between the in vitro study results and clinical data. High glucose can influence on GBM progression through the promotion of the following parameters: cell viability, dispersal, InsR expression and cell proliferation (Ki-67). However, this problem needs more studies and explain the mechanism of action studied drugs.

Tricyclic Antidepressants Modulate Stressed Mitochondria in Glioblastoma Multiforme Cells.

A common feature of solid tumors, including glioblastoma multiforme (GBM), is mitochondrial dysfunction. However, it is reported that the current standard of anti-GBM therapies may potentiate mitochondrial damage and, in effect, support the aggressive character of cancer. As mitochondria are implicated in the modulation of cellular drug sensitivity and chemoresistance mechanisms, activation-stressed mitochondria in GBM cells may represent a new target for anti-GBM therapy that is nontoxic for normal cells. METHODS: As mitochondria are possible targets for antidepressant drugs used as adjuvant therapy in patients with GBM, we examined their influence on mitochondrial volume and activity, reactive oxygen species level, extracellular lactate concentration, and p65 NF-κB gene expression in GBM cells. RESULTS: Our investigation showed, for the first time, that tricyclic antidepressants, imipramine and amitriptyline, partially reverse GBM abnormalities. CONCLUSION: In the light of reported studies, the mitochondrial disturbance observed in glioma cells is a dynamic process that can be reversed or silenced. Moreover, imipramine and amitriptyline are attractive cellular metabolic modulators and can potentially be used to restoring a proper function of mitochondria in GBM cells.

Medicinal Plant Materials in the Treatment of Anxiety Disorders: Neurobiological Aspects.

Context: Pathological anxiety, which affects approximately one-third of the world population, is an inadequate, irrational reaction of an organism to the environment and to a potential threat. Despite advancements in pharmacotherapy for anxiety disorders, further studies are still necessary to search for new substances possessing the desired anxiolytic effects, with as few unwanted effects as possible. Objective: This study intended to examine the characteristics of medicinal plant materials that exhibit anxiolytic properties, with a special emphasis on the mechanisms of action of their active ingredients on the systems involved in the pathophysiology of anxiety. Design: The research team performed a review of the literature, searching well-known online scientific databases, including PubMed, Google Scholar, Medline, ScienceDirect, and SpringerLink. The team searched for the newest research from various regions of the world. Setting: The study was done in the Medical University of Silesia (Katowice, Poland). Results: The medicinal plant materials presented in the current article undoubtedly influence the central nervous system. Our analysis showed that their mechanism of action is very complicated and appropriately still enigmatic. Among them, V officinalis represents the most thoroughly investigated medicinal plant material that produces anxiolytic, sedative effects. However, extracts of other medicinal plants may also emerge as helpful in the treatment of fear and anxiety and in the prophylaxis of those disorders. Conclusions: The current review discusses the most recent data on medicinal plant materials that are effective as anxiolytic treatments, with special emphasis on the neurobiological mechanisms of action of their active ingredients. The research team hopes that the information may open up new directions in the search for drugs capable of enhancing the existing therapy.

Different influence of antipsychotics on the balance between pro- and anti-inflammatory cytokines depends on glia activation: An in vitro study.

The microglial hypothesis of schizophrenia suggests that its neuropathology is closely associated with neuroinflammation manifested, inter alia, by an increased expression of cytokines. However, clinical investigations imply that schizophrenia is a heterogeneous disease and in some groups of patients the activated inflammatory process does not contribute to the disease-associated impairment of brain function. Clinical studies revealed also an equivocal impact of antipsychotics on peripheral and CSF cytokines, whereas experimental research performed on the stimulated glia cultures showed their inhibitory effect on pro-inflammatory cytokine levels. In the present study, the effect of chlorpromazine, haloperidol and risperidone (0.5, 5 or 10µM) on production of pro-inflammatory cytokines IL-1ß and TNF-α and anti-inflammatory IL-10 was investigated in the unstimulated and lipopolysaccharide-stimulated primary rat mixed glial cell cultures. In the unstimulated cultures, haloperidol at all applied concentrations, risperidone at 5, 10µM and chlorpromazine at 10µM increased IL-10 levels in the culture supernatants without a significant influence on IL-1ß or TNF-α levels, and all drugs applied at 10µM induced a robust increase in IL-10 mRNA expression. Under strong inflammatory activation, haloperidol and risperidone at all concentrations reduced production of both pro-inflammatory cytokines, without adverse effects on IL-10 expression when used at 10µM. Chlorpromazine at all concentrations diminished the production of three cytokines and did not induce anti-inflammatory effect. These results suggest that dependently on glia activation antipsychotics via different mechanisms may induce anti-inflammatory effect and that this activity is not common for all drugs under conditions of strong glia activation.

Sex differences in the effect of acute peripheral IL-1ß administration on the brain and serum BDNF and VEGF expression in rats.

The present study was designed to evaluate, for the first time, the potential sex differences in BDNF and VEGF systems under normal conditions and in response to IL-1ß given ip. Peripheral overproduction of this cytokine mediates the pathophysiology of various acute neuroinflammatory states. Until now, the effect of IL-1ß on VEGF expression in rat brain structures and its serum level has not been examined. In male and female rats, the BDNF and VEGF mRNA expression, and BDNF level were evaluated in the amygdala, hippocampus, hypothalamus and pituitary gland. The VEGF levels were determined in the pituitary. Serum BDNF and VEGF levels were also measured. The pituitary BDNF mRNA, and BDNF and VEGF levels were higher in females than in male rats whereas in males, the BDNF levels were higher in the other brain structures. The serum BDNF concentration was similar in both groups but VEGF levels were enhanced in females. Following IL-1ß (50µg/kg ip.) administration, a higher serum IL-1ß level was detected in females than in males. In male rats, IL-1ß decreased BDNF mRNA in all the brain structures, except for the pituitary, and VEGF mRNA in the amygdala. In opposite, IL-1ß challenge in females increased the pituitary VEGF mRNA and serum BDNF and VEGF levels. These results suggest that in females BDNF and VEGF may play a more important role in the pituitary function. In males, amygdala trophic system seems to be especially sensitive to the enhanced peripheral IL-1ß production. Our findings point to the need to consider sex-related differences to be able to draw reliable conclusions about changes in BDNF and VEGF levels during inflammation.

The behavioral and molecular evaluation of effects of social instability stress as a model of stress-related disorders in adult female rats.

The study aimed to test the hypotheses that chronic social instability stress (CSIS) alters behavioral and physiological parameters and expression of selected genes important for stress response and social behaviors. Adult female Sprague-Dawley rats were subjected to the 4-week CSIS procedure, which involves unpredictable rotation between phases of isolation and overcrowding. Behavioral analyses (Experiment 1) were performed on the same rats before and after CSIS (n = 16) and physiological and biochemical measurements (Experiment 2) were made on further control (CON; n = 7) and stressed groups (CSIS; n = 8). Behaviors in the open field test (locomotor and exploratory activities) and elevated-plus maze (anxiety-related behaviors) indicated anxiety after CSIS. CSIS did not alter the physiological parameters measured, i.e. body weight gain, regularity of estrous cycles, and circulating concentrations of stress hormones and sex steroids. QRT-PCR analysis of mRNA expression levels was performed on amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus. The main finding is that CSIS alters the mRNA levels for the studied genes in a region-specific manner. Hence, expression of POMC (pro-opiomelanocortin), AVPR1a (arginine vasopressin receptor), and OXTR (oxytocin receptor) significantly increased in the amygdala following CSIS, while in PFC and/or hypothalamus, POMC, AVPR1a, AVPR1b, OXTR, and ERß (estrogen receptor beta) expression decreased. CSIS significantly reduced expression of CRH-R1 (corticotropin-releasing hormone receptor type 1) in the hippocampus. The directions of change in gene expression and the genes and regions affected indicate a molecular basis for the behavior changes. In conclusion, CSIS may be valuable for further analyzing the neurobiology of stress-related disorders in females.

Desipramine administered chronically inhibits lipopolysaccharide-stimulated production of IL-1ß in the brain and plasma of rats.

Nowadays, it is assumed that therapeutic efficacy of antidepressants depends, at least partly, on their anti-inflammatory properties. The present study investigated for the first time the effect of 21-day oral administration of desipramine on the lipopolysaccharide (LPS)-stimulated IL-1ß concentration in the olfactory bulb, hypothalamus, frontal cortex, hippocampus and plasma of rats, and on the LPS-induced IL-1ß mRNA level in the olfactory bulb. Desipramine (15mg/kg/day) reduced significantly the LPS (250 µg/kg i.p.)-induced IL-1ß concentration in the olfactory bulb, hypothalamus and in plasma, and diminished the LPS effect on IL-1ß mRNA in the olfactory bulb. Plasma concentration of desipramine was comparable to its therapeutic range. By using the α1/α2-adrenoceptor antagonist prazosin and the unspecific ß-adrenoceptor antagonist propranolol given prior to LPS, we found that the effect of desipramine on LPS-induced IL-1ß production was partially mediated by both adrenoceptors in the olfactory bulb and plasma, and that ß-adrenoceptors contributed also to its effect on the stimulated IL-1ß concentration in the hypothalamus. The effect of LPS on the cerebral IL-1ß levels was, in part, mediated by ß-adrenoceptors and, in a region-specific manner, by α1/α2-adrenoceptors. The findings provide evidence for central and peripheral anti-inflammatory activity of desipramine and confirm the impact of the noradrenergic system on IL-1ß production induced by an immunostimulatory challenge.

Superoxide dismutase 1 and glutathione peroxidase 1 are involved in the protective effect of sulodexide on vascular endothelial cells exposed to oxygen-glucose deprivation.

Sulodexide (SDX) is widely used in the treatment of both arterial and venous thrombotic disorders. In addition to its recognized antithrombotic action, SDX has endothelial protective potential, which is independent of the coagulation/fibrinolysis system. However, the detailed molecular mechanisms of the endothelioprotective action of the drug are still unresolved. The aim of the present study was to determine whether treatment with SDX at concentrations of 0.125-0.5 lipase releasing unit (LRU)/ml have on the expression and activity of antioxidant enzymes in ischemic endothelial cells and how these effects might be related to the antiapoptotic properties of SDX. In the present study, human umbilical vein endothelial cells (HUVECs) were subjected to ischemia-simulating conditions (combined oxygen and glucose deprivation, OGD) for 6h to determine the protective effects of SDX. SDX (0.25 and 0.5LRU/ml) in OGD significantly increased the cell viability and prevented mitochondrial depolarization in the HUVECs. Moreover, SDX protected the HUVECs against OGD-induced apoptosis. At concentrations of 0.25 and 0.5LRU/ml, the drug increased both superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPx1) mRNA/protein expression together with a significant attenuation of oxidative stress in ischemic HUVECs. Our findings also demonstrate that an increase in both SOD and GPx activity is involved in the protective effect of SDX on ischemic endothelial cells. Altogether, these results suggest that SDX has a positive effect on ischemia-induced endothelial damage because of its antioxidant and antiapoptotic properties.

How depression and antidepressant drugs affect endocannabinoid system?-review of clinical and preclinical studies.

As major depressive disorder is becoming a more and more common issue in modern society, it is crucial to discover new possible grip points for its diagnosis and antidepressive therapy. One of them is endocannabinoid system, which has been proposed as a manager of emotional homeostasis, and thus, endocannabinoid alterations have been found in animals undergoing various preclinical models of depression procedures as well as in humans suffering from depressive-like disorders. In this review article, studies regarding those alterations have been summed up and analyzed. Another important issue raised by the researchers is the impact of currently used antidepressive drugs on endocannabinoid system so that it would be possible to predict reversibility of endocannabinoid alterations following stress exposure and, in the future, to be able to design individually personalized therapies. Preclinical studies investigating this topic have been analyzed and described in this article. Unfortunately, too few clinical studies in this field exist, what indicates an urgent need for collecting such data, so that it would be possible to compare them with preclinical outcomes and draw reliable conclusions.

A Dot-Blot Screening for Identifying the Temozolomide-Regulated Proteins as Potential Targets for Glioma Multi-OMICS Studies.

BACKGROUND: Malignant gliomas represent a heterogenous group of brain cancers that are characterized by infiltrative growth that lacks a clearly identifiable tumor border. The lack of the possibility of radical surgical resection and targeted therapy results in a poor prognosis. Although Temozolomide (TMZ) is still the leading chemotherapeutic agent in glioma treatment, its efficacy is limited due to the development of tumor resistance. Therefore, there an urgent need to improve the diagnosis and treatment of these tumors. Finding and developing biomarkers that are specific to glioma could be useful for both identifying therapy targets and monitoring treatment as well as for constructing a personalized therapy. However, there are still no reliable markers that would change the quality of glioma treatment. METHODS: In this study, differences in the expression of 84 cancer-related proteins in three glioma cell lines were analyzed using the dot-blot method: commercial T98G cells and two patient-derived cell lines. The influence of TMZ on changes in protein expression, cell morphology, and migration was also investigated (Proteome Profiler Human XL Oncology Array, LeviCell System, Microscopic imaging). The lines that were analyzed were characterized by a remarkably different plasticity of protein expression and the proteomic alterations that were induced by TMZ. RESULTS: A dot-blot analysis revealed ten proteins that were common to all of the lines and five (Cathepsin b, FGF, Survivin, AXL, Osteopontin) that were modulated by the TMZ. As a result of the exposure of TMZ, the proteins that are involved in chemoresistance and invasion (TIE-2, Thrombospondin) were detected in both the HROG02 and T98G cell lines. In the control culture (not exposed to TMZ) of HROG17 cells, the proteins that are involved in metabolism were strongly suppressed. CONCLUSIONS: The presented data sheds new light on the modulatory effect of Temozolomide on the expression of a protein panel: Cathepsin b, fibroblast growth factor (FGF), Survivin, AXL, and Osteopontin that may suggest their potential as therapeutic targets or biomarkers to monitoring therapy effects. However, further high-throughput analysis and detection of the proteins in the body fluids are necessary.

[Carbohydrate sweeteners and obesity]. / Weglowodanowe substancje slodzace a otylosc.

The U.S. prevalence of obesity increases since the mid-70s of the 20th century. Around that time high-fructose corn syrup (HFCS)--mixture of fructose and glucose was introduced as a sweetener replacing sucrose in the food production. HFCS containing 55% fructose and 42-45% glucose (HFCS55) has dominated the American soft drink industry and HFCS has recently become commonly used in Poland. The coincidence of HFCS introduction and obesity epidemic raised widely publicized suspicions of a causal relationship between the two. As a possible mechanism, a higher content of fructose in the HFCS55, as compared with sucrose was suggested -fructose is known to increase serum uric acid level, induce hepatic lipogenesis and not stimulate postprandial hyperinsulinemia, a main activator of leptin release. Few comparative studies of HFCS and sucrose have largely failed to reveal any different impacts on the metabolic parameters, yet they were mainly short-term. It has been recently shown that obesity is linked with changes in the intenstinal flora. Among the causes of allegedly different effects of sucrose and HFCS on metabolism, their influence on the gut microbiome has not been examined. Some bacterial types do not hydrolyze sucrose which may determine different compositions of gut flora with the use of both sweeteners. Studies involving quantitative analysis of bacterial DNA in the stool, both in animals and in humans, shall shed light on the issue that has recently so much absorbed the U.S. public opinion.

Neuropeptides as regulators of the hypothalamus-pituitary-gonadal (HPG) axis activity and their putative roles in stress-induced fertility disorders.

Neuropeptides being regulators of the hypothalamus-pituitary-adrenal (HPA) axis activity, also affect the function of the hypothalamus-pituitary-gonadal (HPG) axis by regulating gonadotrophin-releasing hormone (GnRH) secretion from hypothalamic neurons. Here, we review the available data on how neuropeptides affect HPG axis activity directly or indirectly via their influence on the HPA axis. The putative role of neuropeptides in stress-induced infertility, such as polycystic ovary syndrome, is also described. This review discusses both well-known neuropeptides (i.e., kisspeptin, Kp; oxytocin, OT; arginine-vasopressin, AVP) and more recently discovered peptides (i.e., relaxin-3, RLN-3; nesfatin-1, NEFA; phoenixin, PNX; spexin, SPX). For the first time, we present an up-to-date review of all published data regarding interactions between the aforementioned neuropeptide systems. The reviewed literature suggest new pathophysiological mechanisms leading to fertility disturbances that are induced by stress.

Chronic treatment with escitalopram and venlafaxine affects the neuropeptide S pathway differently in adult Wistar rats exposed to maternal separation.

Neuropeptide S (NPS), which is a peptide that is involved in the regulation of the stress response, seems to be relevant to the mechanism of action of antidepressants that have anxiolytic properties. However, to date, there have been no reports regarding the effect of long-term treatment with escitalopram or venlafaxine on the NPS system under stress conditions. This study aimed to investigate the effects of the above-mentioned antidepressants on the NPS system in adult male Wistar rats that were exposed to neonatal maternal separation (MS). Animals were exposed to MS for 360 min. on postnatal days (PNDs) 2-15. MS causes long-lasting behavioral, endocrine and neurochemical consequences that mimic anxiety- and depression-related features. MS and non-stressed rats were given escitalopram or venlafaxine (10mg/kg) IP from PND 69 to 89. The NPS system was analyzed in the brainstem, hypothalamus, amygdala and anterior olfactory nucleus using quantitative RT-PCR and immunohistochemical methods. The NPS system was vulnerable to MS in the brainstem and amygdala. In the brainstem, escitalopram down-regulated NPS and NPS mRNA in the MS rats and induced a tendency to reduce the number of NPS-positive cells in the peri-locus coeruleus. In the MS rats, venlafaxine insignificantly decreased the NPSR mRNA levels in the amygdala and a number of NPSR cells in the basolateral amygdala, and increased the NPS mRNA levels in the hypothalamus. Our data show that the studied antidepressants affect the NPS system differently and preliminarily suggest that the NPS system might partially mediate the pharmacological effects that are induced by these drugs.

Escitalopram alters the hypothalamic OX system but does not affect its up-regulation induced by early-life stress in adult rats.

We hypothesized that there is a relationship between the orexinergic system (OX) alterations and changes elicited by escitalopram or venlafaxine in adult rats subjected to maternal separation (MS). This animal model of childhood adversity induces long-lasting consequences in adult physiology and behavior. Male Wistar rats from the control and MS groups were injected with escitalopram or venlafaxine (10 mg/kg) IP from postnatal day (PND) 69-89. Adult rats were subjected to behavioral assessment, estimation of hypothalamic-pituitary-adrenal (HPA) axis activity and analysis of the OX system (quantitative PCR and immunohistochemistry) in the hypothalamus and amygdala. MS caused anxiety- and depressive-like behavior, endocrine stress-related response, and up-regulation of the OX system in the hypothalamus. Escitalopram, but not venlafaxine, increased the activity of hypothalamic OX system in the control rats and both drugs had no effect on OXs in the MS group. The disturbed signaling of the OX pathway may be significant for harmful long-term consequences of early-life stress. Our data show that the normal brain and brain altered by MS respond differently to escitalopram. Presumably, anti-anxiety and antidepressant effects of this drug do not depend on the activity of hypothalamic OX system.

[Cultivated oral epithelial cells in oral cavity tissue losses treatment with autologous transplantation--case reports]. / Leczenie ubytków tkanek w jamie ustnej przy pomocy autologicznego przeszczepu nablonka uzyskanego droga hodowli tkankowej--opis przypadków.

UNLABELLED: The rapid development of bioengineering in recent years enables to search for new therapies involving the use of tissue cultures. The aim of this paper is to study and apply the method of keratinocytes culture of mucous membrane on amniotic membrane to cover the losses in the oral cavity. MATERIAL AND METHODS: In four cases keratinocytes culture on amniotic membrane was applied and transplanted to cover antro-oral fistulas and mucosal and mandibular bone losses. RESULTS: Histopathological and immunohistochemistrical examinations of the culture were performed. Cytokeratin 14, protein 63, conexin 43 and IgG were indicated. CONCLUSION: Autologous transplants of epithelial cells on amniotic membrane are a new effective method to cover unhealed tissue losses in oral cavity with the use of modern methods of tissue engineering.

Culture morphology of the autologous cultivated corneal epithelium.

PURPOSE: Ocular surgery based on cultivated corneal epithelium has become a very promising procedure eligible to restore the ocular surface. Analysis of morphologic features and the phenotype of cultivated epithelial cells determines their quality and eligibility of transplantation. MATERIAL AND METHODS: Corneal epithelial cultures were carried out in 25 patients suffering from limbal deficiency after chemical or thermal burns. Fellow healthy eyes were the source of limbal epithelium for the culture. Limbal cells from a 2 mm2 biopsy were seeded on an amniotic membrane after enzymatic pretreatment. Cultures were carried in standard conditions in a supplemented DMEM HAM/F12 medium in the presence of 3T3 fibroblasts. Light microscopy was used to analyze the regularity of the cultivated epithelial layer, histologic examination was used to establish number of epithelial layers, and immunohistochemistry for epithelial and proliferation markers was applied to confirm cell origin and proliferative potential. Staining for cytokeratin 3, 12, 19, connexin 43, and protein p63 was performed. RESULTS: In 25 donors, 27 cultures of the epithelium were performed. In 2 cases, plates were contaminated. Both cultures were repeated. In 84% of the cultures, regular stratified growth of the epithelium with complete covering of amniotic membrane was observed. In 16% of cultures, growth was not regular, showing differences in the number of cell layers. Staining for cytokeratin 3/12 confirmed the corneal origin of cultivated epithelia. The number of epithelial layers ranged from 3 to 9; the average was 5.3 +/- 1.9 layers. CONCLUSION: Cultures of limbal epithelial cells are a valuable source of tissue for restoration of the corneal epithelium.

Are neuropeptides relevant for the mechanism of action of SSRIs?

Selective serotonin reuptake inhibitors (SSRIs) are drugs of first choice in the therapy of moderate to severe depression and anxiety disorders. Their primary mechanism of action is via influence of the serotonergic (5-HT) system, but a growing amount of data provides evidence for other non-monoaminergic players in SSRI effects. It is assumed that neuropeptides, which play a role as neuromodulators in the CNS, are involved in their mechanism of action. In this review we focus on six neuropeptides: corticotropin-releasing factor - CRF, galanin - GAL, oxytocin - OT, vasopressin - AVP, neuropeptide Y - NPY, and orexins - OXs. First, information about their roles in depression and anxiety disorders are presented. Then, findings describing their interactions with the 5-HT system are summarized. These data provide background for analysis of the results of published preclinical and clinical studies related to SSRI effects on the neuropeptide systems. We also report findings showing how modulation of neuropeptide transmission influences behavioral and neurochemical effects of SSRIs. Finally, future research necessary for enriching our knowledge of SSRI mechanisms of action is proposed. Recognition of new molecular targets for antidepressants will have a significant effect on the development of novel therapeutic strategies for mood-related disorders.

Imipramine and Venlafaxine Differentially Affect Primary Glial Cultures of Prenatally Stressed Rats.

Here, we examine the effects of prenatal administration of two antidepressants-imipramine (IMI) and venlafaxine (VEN)-on morphology and activity of a primary glial culture. Microglia are targeted by antidepressants used for antenatal depression and are important regulators of central nervous system development. In this study, female Wistar rats were assigned to one of four groups: a control group that received water ad libitum (1), and groups that received additionally once daily either water (2), IMI (10 mg/kg) (3), or VEN (20 mg/kg) (4) by oral gavage from gestation day 7 to 22. Oral gavage administration induced prenatal stress. Cell cultures were obtained from the brains of 1-day-old pups. Prenatal stress caused a disturbance of sensorimotor function in pups. Prenatal stress also produced alterations in the glial cultures, specifically, an increased percentage of microglia in the mixed glial cultures and an increased percentage of dead cells. Moreover, increased levels of IL1-ß, TNF-α, NO, and an increased expression of CX3CR1 mRNA were found in microglia. However, the ratio of Bax/Bcl2 mRNA was reduced. Prenatal stress increased the vulnerability of microglia to lipopolysaccharide (LPS). The mixed glial culture derived from pups exposed to IMI showed greater morphological changes and the highest percentage of microglia. Microglia were characterized by the largest increase in the production of pro-inflammatory cytokines and NO, and the greatest reduction in the expression of CX3CR1 mRNA. Exposure to IMI reduced the effects of LPS on IL-1ß production and Bax/Bcl2 mRNA, and exacerbated the effects of LPS on CX3CR1 mRNA expression. Prenatal administration of VEN induced protective effects on microglia, as measured by all studied parameters. Taken together, our data suggest that, by disturbing microglia function, exposure to even mild forms of chronic prenatal stress may predispose individuals to psychiatric or neurodevelopmental disorders. These data also indicate that chronic mild stress sensitizes microglia to immune challenges, which may lead to enhanced neuronal damage in the embryonic brain. The observed detrimental effects of IMI on microglial activity under conditions of prenatal stress may help to explain the teratogenic effects of IMI reported in the literature.

Antiapoptotic action of lithium and valproate.

Lithium and valproate (VPA) have been the most widely prescribed mood stabilizers for the therapy of bipolar disorders (BD) for more than 50 years. However, the precise molecular mechanism of their pharmacological activity is not fully known. Recent studies have suggested that both drugs exert antiapoptotic effects. This review focuses on the influence of lithium and VPA on intracellular apoptotic signaling pathways. The active sites, which are implicated in mediating their action, have been described. It has been found that both drugs block the key proapoptotic molecules (GSK-3beta, caspase cascades) and enhance survival pathways (ERK1/2 and Bax proteins). The potential significance of the reported antiapoptotic effects has been discussed.