Neuroprotective effects of aripiprazole in stress-induced depressive-like behavior: Possible role of CACNA1C.

BACKGROUND: Depression is the most common psychiatric disorder. Recently, aripiprazole, a novel antipsychotic drug, has been approved as the adjunctive therapy for the Treatment-Resistant Depression (TRD). However, the mechanisms underlying the antidepressant effects of aripiprazole are not fully known. Besides the involvement of calcium signaling dysregulations in the pathophysiology of depression, there is some evidence of overexpressed CACNA1C (the gene encoding the Cav1.2 channels) following chronic stress in the brain regions, which involved in emotional and stress responses. Based on the data indicating the aripiprazole's effects on intracellular calcium levels, this study aimed to investigate the mechanisms of therapeutic effects of aripiprazole, by a focus on the modulation of CACNA1C expression, in the rat stress-induced model of depression. METHODS: Using Chronic Unpredictable Mild Stress (CUMS) model of depression, we examined the effects of aripiprazole on depressive and anxiety-like behaviors (by forced swimming test and elevated plus maze), serum IL-6 (Elisa), and cell survival (Nissl staining). In addition, CACNA1C, BDNF, and TrkB expression in the PFC and hippocampus (RT-qPCR), as well as BDNF and GAP-43 protein levels in the hippocampus (Immunohistofluorescence), have been assayed. RESULTS: Our data indicated that aripiprazole could improve anxiety and depressive-like behaviors, decrease the serum levels of IL-6 and hippocampal cell death following CUMS. In addition, we showed the significant modulation on overexpressed CACNA1C, as well as downregulated BDNF and GAP-43 expression DISCUSSION: These results demonstrate that aripiprazole may promote synaptic plasticity by improving the expression of BDNF and gap-43. In addition, inflammation reduction and CACNA1C expression downregulation may be some of mechanisms by which aripiprazole alleviates chronic stress-induced hippocampal cell death and play its pivotal antidepressant role.

Fluoxetine increases hippocampal neural survival by improving axonal transport in stress-induced model of depression male rats.

INTRODUCTION: Axonal transport deficit is a key mechanism involved in neurodegenerative conditions. Fluoxetine, a commonly used antidepressant for treatment of depression, is known to regulate several important structural and neurochemical aspects of hippocampal functions. However, the mechanisms underlying these effects are still poorly understood. This study aimed to investigate the effects of chronic fluoxetine treatment on axonal transport in the hippocampus of rat stress-induced model of depression. METHODS: We have analyzed the effects of chronic fluoxetine treatment (20 mg/kg/day, 24 days) on immobility behavior (forced swimming test), hippocampal iNOS (inflammatory factor) expression (RT-PCR) as well as hippocampal BDNF, kinesin and dynein expression (RT-PCR) and hippocampal neuronal survival (Nissl staining). RESULTS: This study provided evidence that fluoxetine could effectively suppress iNOS expression following unpredictable chronic mild stress (P < 0.01), increase hippocampal BDNF (P < 0.01), kinesin (P < 0.05) and dynein (P < 0.01) gene expression, and control neuronal death in CA1 (P < 0.01) and CA3 regions (P < 0.01) of the hippocampus and thereby improve immobility behavior (P < 0.001). CONCLUSION: Based on the findings of this study, we concluded the neuroprotective effect of fluoxetine may be due to its ability to improve axonal transmission, followed by increased energy supply and neurotrophin concentration and function.

Neuroprotective effects of cerium oxide nanoparticles on experimental stress-induced depression in male rats.

INTRODUCTION: Inflammation and oxidative/nitrative stress induced by chronic psychosocial or physical stress play fundamental roles in the pathogenesis of depression, and lead to the loss of neurotrophic support, decreased neurogenesis and synaptic plasticity in the hippocampus. Findings have shown inhibition of inflammation waterfall may offer new approaches to the treatment of depression, especially for patients with treatment-resistant depression (TRD). Cerium Oxide (CeO2) is the oxide form of cerium, a rare earth element in the lanthanide series. Cerium oxide nanoparticles (CeO2NPs) are potent regenerative antioxidant and anti-inflammatory agents. We evaluated the neuroprotective and the neuronal plasticity activities of CeO2NPs in the stress-induced model of depression. METHODS: We have analyzed the effects of single-dose intrahippocampal and intracerebroventricular (ICV) injections of CeO2NPs treatment on immobility behavior (forced swimming test), hippocampal IL-6 and malondialdehyde (Elisa), cell survival (Nissl staining), dentate gyrus BrdU-positive cells (Immunohistofluorescence) and growth associated protein-43 (GAp-43) expression (Immunohistofluorescence) of the hippocampal CA3 region. RESULTS: In our study, single-dose CeO2NPs treatment could effectively suppress inflammatory and oxidative markers level induced by unpredictable chronic mild stress (UCMS) and improved immobility behavior, increased hippocampal cell proliferation, cell survival and neurite outgrowth, and thereby, prevented the progression of hippocampal destruction and dysfunction. CONCLUSION: This study demonstrates a new prospect for the treatment of depression. Our study gives us the confidence to continue the investigation of CeO2 NPs as a novel therapy, especially, for TRD that characterized by chronic and persistent inflammation.

Valproic acid administration exerts protective effects against stress-related anhedonia in rats.

Anhedonia or inability to experience pleasure is the sign of various neuropsychiatric conditions. Current treatment options do not provide adequate control of anhedonia. The present study was conducted to evaluate the protective effects of valproic acid (VPA) as a nonspecific histone deacetylase (HDAC) inhibitor to reverse the effects of stress on induction of anhedonia and explore possible mechanisms. To induce anhedonia, a rat model of chronic unpredictable mild stress (CUMS) was established. Animals were assigned into no stress, stress (6 weeks of CUMS) and two treatment groups. VPA treatment was carried out for 4 continuous weeks (200 mg/kg/day). Behavioral assessments were performed using sucrose consumption (SCT) and new object recognition (NOR) tests. The expression of genes was evaluated using qRT-PCR. The cell density was determined using Nissl staining. Rats with CUMS showed depressive-like behaviors and impaired memory performance compared with the non-stressed group (p < 0.01). Moreover, they had significantly higher levels of HDAC3 and MC4R expression in the nucleus accumbens (NAc) compared to the non-stressed group (p < 0.01). The NAc cell density was significantly higher in the non-stressed rats (p < 0.05). Corticosterone plasma level was increased in the CUMS compared to the non-stressed group (p < 0.05). In the CUMS + VPA subgroup, the corticosterone (CORT) plasma level was lower compared with the CUMS + Saline and/or the CUMS groups (p < 0.05). These findings suggest that VPA can improve anhedonia and stress. Although the protective effect of VPA might link to decreasing HDAC3 and MC4R genes expression in NAc.

Diabetic Encephalopathy Affecting Mitochondria and Axonal Transport Proteins.

INTRODUCTION: Diabetic encephalopathy is described as any cognitive and memory impairments associated with hippocampal degenerative changes, including the neurodegenerative process and decreased number of living cells. Mitochondrial diabetes (MD) appears following activation of mutant mitochondrial DNA and is a combination of diabetes and cognitive deficit. In this research, we showed the correlation of diabetic encephalopathy, dysfunctional mitochondria, and changes in the expression of axonal transport proteins (KIF5b, Dynein). METHODS: Twenty-four male Wistar rats were divided into three groups: (n=8 in each group):1. Control + saline; 2. Diabetic, and 3. Diabetic + insulin. Before starting the experiments, the animals with blood sugar lower than 150 mg/dL entered the study. Diabetes induction was carried out by Intraperitoneal (IP) Streptozotocin (STZ) administration. Fasting Blood Sugar (FBS) and body weight was checked after the first week and at the end of the eighth week. Then, behavioral studies (elevated plus maze, Y-maze, and passive avoidance learning) were performed. After behavioral studies, blood samples were taken to measure serum insulin level and HgbA1c. Next, fresh hippocampal tissue was collected. Gene expression of motor proteins was assessed by real-time PCR and mitochondrial membrane potential by rhodamine123. RESULTS: Our results showed the impairment of HgbA1c, serum insulin, FBS, and weight in the diabetic group (P<0.05). Behavioral tests revealed different degrees of impairment in diabetic rats (P<0.05). KIF5b mRNA expression increased in the hippocampus (P<0.05) with no change in dynein gene expression. These changes were associated with abnormal mitochondrial membrane potential (P<0.05). CONCLUSION: KIF5b mRNA up-regulation in hippocampal neurons of STZ-diabetic rats is a factor that can be involved in abnormal axonal transport and decreased MMP, leading to impairment of mitochondrial function. These manifestations showed mitochondrial dysfunction in diabetes and resulted in abnormal behavioral tests and diabetic encephalopathy.

Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation.

INTRODUCTION: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models. METHODS: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200-250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6. RESULTS: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline. CONCLUSION: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.

Ibuprofen Protection Against Restrained Chronic Stress-induced Depression in Male Rats.

INTRODUCTION: Stress predisposes organisms to depression and cognitive impairments, and seems to interact with metabolic homeostasis. The inflammatory response and the upregulation of proinflammatory cytokines are some of the consequences related to chronic stress. In this study, we investigated the preventive effect of chronic administration of ibuprofen, as an inhibitor of cyclooxygenases, on the cognitive and behavioral alterations and the weight gain reduction induced by simultaneous chronic restraint stress in rats. MATERIALS AND METHODS: Male Wistar rats were subjected to chronic restraint stress and injected daily with the variable doses of ibuprofen or vehicle, for 21 consecutive days. Then, all animals were tested with the forced swim test and passive avoidance conditioning. Also, the weight of the animals was recorded before and after the interventions. Ultimately, plasma interleukin 6 (IL-6) levels were measured. RESULTS: Chronic stress increased depressive-like behaviors, impaired learning, and disrupted the normal weight gain. However, the animals that received the highest dose of ibuprofen showed less depressive-like behaviors, a better avoidance memory, and a higher weight gain. However, the level of plasma IL-6 did not differ significantly between the study groups. CONCLUSION: The administration of ibuprofen prevents the cognitive and behavioral consequences of chronic stress. During the recovery, the plasma levels of IL-6 were not elevated by stress, and the IL-6 levels did not predict the behavioral performance of the stressed animals. The exact mechanisms of the protective effects of ibuprofen against chronic stress need to be further investigated.

Deferoxamine regulates neuroinflammation and oxidative stress in rats with diabetes-induced cognitive dysfunction.

Diabetic encephalopathy, a major complication of diabetes, is characterized by cognitive impairment and structural and neurochemical abnormalities. Neuroinflammation following impairment of iron homeostasis is a remarkable feature of several neurological disorders. In the present study, we investigated the role of deferoxamine (DFO), as a clinical iron chelator, in improvement of type 1 diabetes-induced cognitive dysfunction. Streptozotocin was utilized to induce type 1 diabetic in rat model. Animals were categorized into four groups: control, diabetic, diabetic + Iron and diabetic + DFO. Hence, DFO was administered at a dose of 100 mg/kg S.C and iron was administered at a dose of 12 mg/kg P.O for 8 weeks. Finally, Y-maze and passive avoidance were performed. Measurement of IL-6, ferritin, and the brain-derived neurotrophic factor (BDNF) expression was carried out using ELISA. Our results showed significant increased levels of ferritin (P < 0.001), IL-6 (P < 0.001), MDA (P < 0.01), as well as decreased levels of BDNF (P < 0.001) in the diabetic and iron groups compared to control. Post-treatment with DFO for 8 weeks after the induction of diabetes, markedly reduced levels of ferritin (P < 0.001), IL-6 (P < 0.01), and MDA (P < 0.001), as well as increased levels of BDNF (P < 0.01) compared to the diabetic and iron groups was observed. Collectively, these findings demonstrate the validity of DFO as a good candidate to attenuate cognitive dysfunction following diabetes by targeting oxidative stress, neuroinflammation, and modulation of iron homeostasis.

Fluoxetine attenuates stress-induced depressive-like behavior through modulation of hippocampal GAP43 and neurogenesis in male rats.

Based on the monoaminergic theory, Serotonin-Selective Reuptake Inhibitors (SSRIs) are used for treating depression. Recent hypotheses suggest that antidepressants may influence neurogenesis and synaptic plasticity. However, the mechanisms underlying these effects are still poorly understood. The aim of the present study was to evaluate the effect of fluoxetine, a widely used SSRI antidepressant, on the neurogenesis and the expression of Growth-Associated Protein 43 (GAP43), a synaptic protein, in the rat hippocampus exposed to Unpredictable Chronic Mild Stress (UCMS; the model of depressive-like behavior). We have analyzed the effects of chronic fluoxetine treatment on immobility behavior (forced swimming test), plasma interleukin-6 and corticosterone (enzyme-linked immunosorbent assay), BrdU-positive cells in the dentate gyrus and GAP43 expression in the CA3 region (Immunohistochemistry) of the hippocampus. This study provides evidence that fluoxetine is a potent enhancer of GAP-43, a protein related to the neuronal plasticity, in the hippocampus of the rat model of depression. Interestingly, our results showed that although fluoxetine significantly is effective in increasing BrdU positive cells, it is more effective in increasing the neurite formation compared with neurogenesis. The results support the idea that antidepressants can promote neuronal plasticity. We concluded that the increase of GAP-43- induced neurite formation may be an important mechanism by which fluoxetine augments hippocampal neuroplasticity and play its pivotal antidepressant role.

Axonal transport proteins and depressive like behavior, following Chronic Unpredictable Mild Stress in male rat.

BACKGROUND: A common mood disorder, depression has long been considered a leading cause of disability worldwide. Chronic stress is involved in the development of various psychiatric diseases including major depressive disorder. Stress can induce depressive-like symptoms and initiate neurodegenerative processes in the brain. The neurodegenerative theory of depression holds impaired axonal transport as a negative factor in neural survival. Axonal transport is a critical mechanism for normal neuronal function, playing crucial roles in axon growth, neurotransmitter secretion, normal mitochondrial function and neural survival. METHODS AND MATERIALS: To investigate the effects of stress-induced depression, in the present study, we evaluated behavior by forced swimming test (FST), corticosterone plasma level by ELISA assay, hippocampal mRNA expression of three genes (NGF, kinesin and dynein) via real-time PCR and hippocamp count by Nissl staining in male Wistar rats. RESULTS: Our data demonstrated a significant decrease in the expression of NGF, kinesin and dynein genes in CUMS groups compared to the control group (non-stressed) (p < 0.05). CUMS also caused an elevation in immobility time and corticosterone plasma level in the stressed group compared to the controls (p < 0.01 and p < 0.05, respectively). CONCLUSION: The results suggested that the possibility of stress-induced depressive behavior associated with hippocampal neurodegeneration process is correlated with a low expression of kinesin and dynein, the two most important proteins in axonal transport.

The Effect of Luteinizing Hormone Reducing Agent on Anxiety and Novel Object Recognition Memory in Gonadectomized Rats.

INTRODUCTION: Mood disorders such as anxiety and depression are common following menopause and andropause. Lack of sex steroid hormones is suggested as the primary cause of these disturbances. The level of luteinizing hormone (LH) would also rise 3-4 times than normal in these people. The potential effects of LH on mood and cognitive symptoms following menopause and andropause are still unknown. This study aimed to investigate the effect of increased LH on novel object discrimination (NOD) memory and anxiety like behavior in gonadectomized rats. METHODS: Four-month-old male and female Wistar rats were randomly assigned into 4 groups (in each sex): control rats (Cont), gonadectomized without treatment (GnX), gonadectomized treated with triptorelin, a GnRH agonist which reduces LH release eventually, (GnX+Tr), gonadectomized treated with triptorelin plus sex steroid hormone, estradiol in female and testosterone in male rats (GnX+Tr+S/T). After 4 weeks treatment, anxiety score (elevated plus maze) and NOD were measured. Data were analyzed using One-way ANOVA, and P-values less than 0.05 were considered as significant. RESULTS: Gonadectomy increased anxiety like behaviors (decrease of presence time in the open arms) in female rats (P=0.012), but not in male ones (P=0.662). Additionally, triptorelin alone reduced the increased anxiety score in gonadectomized female rats, compared to group treated with both triptorelin and estradiol. Furthermore, it was shown that gonadectomy and or treatment with triptorelin and sex steroids had no significant effect on novel object recognition memory in both female (P=0.472) and male rats (P=0.798). CONCLUSION: Findings of this study revealed that increased level of LH following menopause or andropause should be considered as a possible cause for increased anxiety. Also, this study showed that LH reducing agents would reduce anxiety like behavior in gonadectomized female rats. The effect of increased LH on cognitive functions such as novel object recognition memory was not evident in this study and needs further studies.

Hippocampal NR3C1 DNA methylation can mediate part of preconception paternal stress effects in rat offspring.

Many studies have been shown that maternal stress during pregnancy and in early life period influences offspring in the behavioral and molecular aspects in human and animal models. Recent research has indicated that the environmental condition of males before conception has effects on next generations. We evaluated whether preconception paternal stress (PPS) could influence on hippocampal glucocorticoid receptor gene (GR), (NR3C1) expression, corticosterone response and behavioral outcomes of their offspring. For this purpose, adult male rats were subjected to daily 10min session of forced swimming for 21 consecutive days. Then, two parental breeding groups were formed: stressed father (SF) and non-stressed father (NSF) or control group. 30-day-old pups were tested for anxiety-like behavior by using the elevated plus maze (EPM). Serum corticosterone level was also measured by ELISA. Hippocampal NR3C1 DNA methylation, gene and protein expression were respectively assayed by methylation sensitive restriction enzymes (Real Time PCR), Reverse Transcriptase PCR (RT-PCR) and Western-blotting in all groups. More anxiety-related behavior, serum corticosterone concentration, DNA methylation levels of NR3C1 and lower expression of this gene were significantly observed in paternally stressed pups compared to control pups. As well, molecular changes were more pronounced in male pups compared to female pups. Our results revealed that paternal stress prior to conception has a negative effect on molecular, hormonal and behavioral outcomes in their offspring.

Effect of Maternal Stress Prior to Conception on Hippocampal BDNF Signaling in Rat Offspring.

Environmental factors, especially stress, can remain pervasive effects across the lifespan. Traumatic experiences are risk factors for the behavioral and emotional disorders. Since brain-derived neurotrophic factor (BDNF) is the important regulator of neural survival, development, and its genetic and epigenetic alterations which have been linked with several neuropsychiatric disorders, the present study investigated the effect of maternal adulthood stress on molecular changes of BDNF and tyrosine kinase-coupled receptor (TrkB) in the hippocampus of 30-day-old offspring. To induce stress, we employed a repeated forced swimming model for female rats across 21 days. Then, they were divided into two parental breeding groups: stressed mother (SM) and non-stressed mother (NSM) or control group. Anxiety-like behavior was tested in adult female rats and 30-day-old pups by using the elevated plus maze (EPM). The level of serum corticosterone was also measured by ELISA. BDNF and TrkB gene methylation and protein expression in the hippocampus were detected using real-time PCR and Western blotting in all groups. Thirty-day-old male and female pups from SM groups had a significantly more serum corticosterone concentration, DNA methylation levels of BDNF and TrKB, and lower expression of these genes compared to pups from the control groups. Also, male pups from stressed mother exhibited significant anxiety-like behavior compared to male pups from the control mothers. These findings suggest that molecular changes formed by maternal stress experience even before conception persist to the next generation and will negatively influence on phenotypes of offspring.

Comparison of the Adulthood Chronic Stress Effect on Hippocampal BDNF Signaling in Male and Female Rats.

Studies show that gender plays an important role in stress-related disorders, and women are more vulnerable to its effect. The present study was undertaken to investigate differences in the change in expression of brain-derived neurotrophic factor (BDNF), and its tyrosine intracellular kinase-activating receptor (TrkB) genes in the male and female rats' hippocampus (HPC) under chronic mild repeated stress (CMRS) conditions. In this experiment, male and female Wistar rats were randomly divided into two groups: the CMRS and the control group. To induce stress, a repeated forced swimming paradigm was employed daily for adult male and female rats for 21 days. At the end of the stress phase, elevated plus maze (EPM) was used for measuring the stress behavioral effects. Serum corticosterone level was measured by ELISA. BDNF and TrkB gene methylation and protein expression in the HPC were detected using real-time PCR and Western blotting. Chronic stress in the adolescence had more effects on anxiety-like behavior and serum corticosterone concentration in female rats than males. Furthermore, stressed female rats had higher methylation levels and following reduced protein expression of BDNF but not TrkB compared to stressed male rats. These findings suggest that in exposure to a stressor, sex differences in BDNF methylation may be root cause of decreased BDNF levels in females and may underlie susceptibility to pathology development.

The role of hepcidin in chronic mild stress-induced depression.

Depression is one of the most prevalent challenges of mental conditions. Yet its exact etiology has not been clear. Chronic stress increases the production of cytokines, which can lead to depression. Hepcidin, an iron modulator, is involved in the inflammation process as well as iron homeostasis. This study was designed to investigate the role of hepcidin, on stress-induced depression. 60 male wistar rats were entered the experiment. We used a chronic unpredictable mild stress (for 28 days) as a rat model of depression. In stressed group, three subgroups were treated with three different doses of dalteparin (a hepcidin inhibitor): 70IU/kg, 100IU/kg and 140IU/kg daily, for 4 weeks. The animals in the stressed group had more depressive-like behavior than the control group. Moreover, chronic mild stress produced an increased serum interleukin-6 levels. These effects were accompanied by an obvious increase in hepcidin mRNA level and iron content in the hippocampus. These changes were blocked by the injection of dalteparin. In conclusion, inhibition of hepcidin may reduce many pathological changes seen in stress-induced depressive disorders.

Iron administration prevents BDNF decrease and depressive-like behavior following chronic stress.

Pro-inflammatory cytokines play important roles in responses to stresses and affect iron metabolism. Iron is essential for survival of hippocampus neurons and plays a role in depression. Noting the close causal effect relation between stress and depression, in this experimental study we investigated the influence of iron on stress-induced depression. Rats were exposed to chronic mild stress and were treated with three different iron doses (9, 12, and 20mg/kg) three times a week for four weeks with an iron chelator in the first and third week. Serum interleukin-6 (enzyme-linked immune sorbent assay), hippocampus iron content (atomic absorption spectrometry), brain-derived neurotrophic factor (BDNF) gene expression (real-time polymerase chain reaction), CA1 pyramidal cell count (Nissl method) and a behavioral test (forced swimming test) were evaluated. In both the stressed and stressed plus iron groups, hippocampus cell counts were lower than in the control group (non-stressed). The use of deferiprone in the stressed groups markedly prevented neuronal loss. In stressed rats, the iron content of the hippocampus was higher than in the control group (P<0.001). Moreover, in the stressed group with moderate iron administration (12 mg/kg), there was a significant elevation of BDNF expression (P<0.05) and decreased immobility behavior time (P<0.05). These results indicate that high doses of iron in stressful situations augment neuronal degeneration and loss, possibly by iron accumulation. Deferiprone as an iron chelator could reverse this effect. During chronic mild stress, cerebrospinal fluid possibly reduces the iron content and may result in reduction of monoamines being involved in mood regulation. Iron administration in a moderate dose can increase these neurotransmitters and BDNF expression.

Cognitive impairment induced by permanent bilateral common carotid occlusion exacerbates depression-related behavioral, biochemical, immunological and neuronal markers.

There is a strong link between cognitive impairment and depression, but up to date it is not clear whether cognitive impairment is 'cause' or 'consequence' of depression. Therefore, we here examined the effect of cognitive impairment induced by permanent occlusion of common carotid arteries, a model known as two-vessel occlusion (2VO), on chronic unpredictable stress (CUS)-induced depression-related markers in rats. Male Sprague-Dawley rats underwent 2VO or sham surgery. Sixty days after the surgery, the cognitive function of the rats was tested using the radial arm maze task measuring working and reference memory. Subsequently, the animals were randomly assigned to undergo 21 days of CUS or to stay non-stressed. One week after the last stressor, psychomotor retardation, a feature of depression-like behavior, was assessed using the forced swim test (FST) by measuring time spent on immobility. Plasma amino acid (glutamine, glutamate and glycine) and serum pro-inflammatory cytokine (interleukin 6) levels, and hippocampus CA1 neuronal damage were measured 24h after FST exposure. Results show that 2VO increased immobility in the FST only when rats had been exposed to CUS. In addition, 2VO surgery intensified the effect of CUS on IL-6, glutamate and glycine levels and increased CA1 hippocampal damage. In conclusion, our findings show that cognitive impairment may predispose to depression by intensifying the effect of stress on depression-related behavioral, biochemical, immunological and neuronal markers.

Parents' adulthood stress induces behavioral and hormonal alterations in male rat offspring.

Exposure to stress can influence hypothalamo-pituitary-adrenal (HPA) axis in mammals and impair their behavioral/hormonal development. Stress during fetal or early life may have wide range effects on the offspring phenotype in rodents. Since the role of parents' adulthood stress before mating is not fully understood yet, we investigated the effects of parents' adulthood stress on behavioral and hormonal parameters in 10- and 30-day-old male offspring. To induce stress in the adult male and female rats, a repeated forced swimming paradigm was employed daily over the course of 21 days. Then, they were categorized into four parental breeding groups: stressed parents (SP), stressed mother (SM), stressed father (SF) and non-stressed parents (NSP). Anxiety-like behavior was tested in adult rats and 30-day-old male pups, using the elevated plus maze (EPM). The level of serum corticosterone was measured by ELISA in all groups. Stressed adult rats showed enhanced serum corticosterone concentration and anxiety-like behavior. Serum corticosterone level of the 10- and 30-day-old pups of the SP, SM and SF groups was significantly higher than pups from the non-stressed group. Furthermore, 30-day-old pups of the SP, SM and SF groups had lower time spent in the open arms compared to the control group, but stress had no significant effects on the percent of entries into the open arms. In addition, serum corticosterone level in 30-day-old pups were raised by a stressed mother was markedly more than 10-day-old pups. These findings revealed that parents' adulthood stress have negative impacts on behavioral and hormonal responses of their male offspring.

Pimecrolimus 1 percent cream and pulsed dye laser in treatment of a patient with reticular erythematous mucinosis syndrome.

We report on the efficacy of twice daily application of pimecrolimus 1 percent cream in a 48-year-old woman with reticular erythematous mucinosis (REM) syndrome and compare its results with pulsed dye laser (PDL) on the other side of her chest and back. The patient was previously treated by hydroxychloroquine but only a fair response was observed. After application of 5 months of pimecrolimus, the lesions completely resolved and the result was comparable with the other side of her body treated by pulsed dye laser PDL. Topical pimecrolimus and pulsed dye laser appear to be effective and safe treatments for REM.

Role of nitric oxide in the gastro-protective effect of lithium.

BACKGROUND AND AIM: Lithium is widely used for the management of neuropsychiatric symptoms in bipolar disorders. A few studies have shown that lithium has a protective effect against gastric damage with an unknown mechanism. Some of the actions of lithium are mediated through nitric oxide (NO), which has an important role in the regulation of gastric wall blood flow as well as gastric mucosal integrity. The aim of this study was to test the hypothesis if the gastro-protective effect of lithium is mediated through NO. METHODS: Male Wistar rats were pre-treated with either a non-selective NO synthase inhibitor (N(G)-nitro-l-arginine, 10mg/kg), a selective inducible NO synthase inhibitor (aminoguanidine, 100mg/kg) or saline. Lithium carbonate (10, 20, 50 and 100mg/kg) was then administered intraperitoneally 1h before the induction of gastric mucosal damage. Gastric damage was induced by either water immersion stress or ethanol gavage in rats. RESULTS: Lithium had a significant protective effect in both stress and ethanol-induced gastric damage, but it needed in ethanol-induced gastric damage a higher dose than in the stress induced lesion. Lithium carbonate doses 20 and 50mg/kg produced plasma concentrations that were in the range of human therapeutic Li levels (0.6-1.0muM). Pre-treatment of animals with N(G)-nitro-l-arginine (20 and 40mg/kg) reduced the protective effect of lithium against ethanol-induced gastric damage, but not in stress-induced damage. Aminoguanidine administration showed no effect on the damage reduction either in control or lithium treated rats. CONCLUSIONS: The results indicate that NO might play a role in the gastro-protective effect of lithium against ethanol-induced gastric damage in rats.