Olanzapine alters the expression of gasotransmitter-related enzymes: CBS and HO-2 in the rat hippocampus and striatum.

BACKGROUND: Gaseous neurotransmitters have been thought to be novel factors involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about the potential crosstalk between neuronal gasotransmitter signaling and neuroleptics action. The present work was, therefore, focused on gene expression of H2S and CO-producing enzymes in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at a dose of 5 mg/kg daily). All individuals were sacrificed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain and for quantitative analysis of cystathionine ß-synthase (CBS) and heme oxygenase 2 (HO-2) protein distribution in selected brain structures. RESULTS: Long-term treatment with olanzapine is reflected in different changes in the number of enzymes-expressing cells in the rat brain. Olanzapine decreased the number of CBS-expressing cells and possibly reduced H2S synthesis in the hippocampus and striatum. The antipsychotic administration increased the number of HO-2 immunopositive cells and probably stimulated the CO production in the hippocampus. CONCLUSIONS: Modulatory effect of olanzapine on cellular mechanisms of gasotransmitter synthesis may be an alternative way of their pharmacological action.

Modulatory effect of long-term treatment with escitalopram and clonazepam on the expression of anxiety-related neuropeptides: neuromedin U, neuropeptide S and their receptors in the rat brain.

BACKGROUND: Newly identified multifunctional peptidergic modulators of stress responses: neuromedin U (NMU) and neuropeptide S (NPS) are involved in the wide spectrum of brain functions. However, there are no reports dealing with potential molecular relationships between the action of diverse anxiolytic or antidepressant drugs and NMU and NPS signaling in the brain. The present work was therefore focused on local expression of the aforementioned stress-related neuropeptides in the rat brain after long-term treatment with escitalopram and clonazepam. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 3 groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 5 mg/kg daily), and clonazepam (at single dose 0.5 mg/kg). All individuals were sacrificed under anaesthesia and the whole brain excised. Total mRNA was isolated from homogenized samples of amygdala, hippocampus, hypothalamus, thalamus, cerebellum and brainstem. Real time-PCR method was used for estimation of related NPS, NPS receptor (NPSR), NMU, NMU and receptor 2 (NMUR2) mRNA expression. The whole brains were also sliced for general immunohistochemical assessment of the neuropeptides expression. RESULTS: Chronic administration of clonazepam resulted in an increase of NMU mRNA expression and formation of NMU-expressing fibers in the amygdala, while escitalopram produced a significant decrease in NPSR mRNA level in hypothalamus. Long-term escitalopram administration affects the local expression of examined neuropeptides mRNA in a varied manner depending on the brain structure. CONCLUSIONS: Pharmacological effects of escitalopram may be connected with local at least partially NPSR-related alterations in the NPS/NMU/NMUR2 gene expression at the level selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade.

BACKGROUND: Neuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular interactions between the activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in the context of adult neurogenesis and the expression of noncanonical stress-related neuropeptides such as neuromedin U (NMU). The present work therefore focused on immunoexpression of neuromedin U receptor 2 (NMUR2) and doublecortin (DCX) in the rat hippocampus after acute treatment with escitalopram and in combination with selective neuropeptide S receptor (NPSR) blockade. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into five groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 10 mg/kg daily), escitalopram + SHA-68, a selective NPSR antagonist (at single dose 40 mg/kg), SHA-68 alone, and corresponding vehicle control. All animals were sacrificed under halothane anaesthesia. The whole hippocampi were quickly excised, fixed, and finally sliced for general qualitative immunohistochemical assessment of the NPSR and NMUR2 expression. The number of immature neurons was enumerated using immunofluorescent detection of doublecortin (DCX) expression within the subgranular zone (SGZ). RESULTS: Acute escitalopram administration affects the number of DCX and NMUR2-expressing cells in the adult rat hippocampus. A decreased number of DCX-expressing neuroblasts after treatment with escitalopram was augmented by SHA-68 coadministration. CONCLUSIONS: Early pharmacological effects of escitalopram may be at least partly connected with local NPSR-related alterations of neuroblast maturation in the rat hippocampus. Escitalopram may affect neuropeptide and DCX-expression starting even from the first dose. Adult neurogenesis may be regulated via paracrine neuropeptide S and NMU-related signaling.

Chlorpromazine affects the numbers of Sox-2, Musashi1 and DCX-expressing cells in the rat brain subventricular zone.

BACKGROUND: Adult neurogenesis observed both in the subventricular zone (SVZ) and hippocampus may be regulated and modulated by several endogenous factors, xenobiotics and medications. Classical and atypical antipsychotic drugs are able to affect neuronal and glial cell proliferation in the rat brain. The main purpose of this structural study was to determine whether chronic chlorpromazine treatment affects adult neurogenesis in the canonical sites of the rat brain. At present, the clinical application of chlorpromazine is rather limited; however, it may still represent an important model in basic neuropharmacological and toxicological studies. METHODS: The number of neural progenitors and immature neurons was enumerated using immunofluorescent detection of Sox2, Musashi1 and doublecortin (DCX) expression within SVZ. RESULTS: Chlorpromazine has a depressive effect on the early phase of adult neurogenesis in the rat subventricular zone (SVZ), as the mean number of Sox-2 immunoexpressing cells decreased following treatment. CONCLUSION: Collectively, these results may suggest that long-term treatment with chlorpromazine may decrease neurogenic stem/progenitor cell formation in the rat SVZ and may affect rostral migratory stream formation.

Spexin-expressing neurons in the magnocellular nuclei of the human hypothalamus.

Neuropeptides are involved in numerous brain activities being responsible for a wide spectrum of higher mental functions. The purpose of this concise, structural and qualitative investigation was to map the possible immunoreactivity of the novel neuropeptide spexin (SPX) within the human magnocellular hypothalamus. SPX is a newly identified peptide, a natural ligand for the galanin receptors (GALR) 2/3, with no molecular structure similarities to currently known regulatory factors. SPX seems to have multiple physiological functions, with an involvement in reproduction and food-intake regulation recently revealed in animal studies. For the first time we describe SPX expressing neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the human hypothalamus using immunohistochemical and fluorescent methods, key regions involved in the mechanisms of osmotic homeostasis, energy expenditure, consummatory behaviour, reproductive processes, social recognition and stress responses. The vast majority of neurons located in both examined neurosecretory nuclei show abundant SPX expression and this may indirectly implicate a potential contribution of SPX signalling to the hypothalamic physiology in the human brain.

Exposure to lead affects male biothiols metabolism.

The most important biothiols include glutathione, homocysteine (HCY), cysteine and proteins. The aim of the presented study was to evaluate the influence of lead on the biothiol turnover--the concentration of HCY and protein sulfhydryl groups (P-SH) in the serum and reduced glutathione (G-SH) in erythrocytes--in individuals (employees of metal works) exposed to lead and to evaluate its probable oxidative disorders, measured as the carbonyl protein (CP) concentration in serum. The exposed workers were divided into 2 subgroups: 1) low lead exposure (LPb), with a lead concentration in the blood (PbB) of 20-45 µg dl(-1) (n= 102), and 2) high lead exposure (HPb), with PbB = 45-60 µg dl(-1) (n= 81). The control group consisted of 72 office workers or other healthy subjects with no history of occupational exposure to lead. All the controls had normal PbB (<10 µg dl(-1)) and ZPP (<2.5 µg dl(-1)) levels. The concentration of HCY was higher in the LPb group by 11% and in the HPb group by 26%, compared with the control group (n=72). The CP concentration in these 2 groups was more than twice as high as that of the control group, with 108% and 125% increases for the LPb and HPb groups, respectively; G-SH was lower by 6.6% and 7.4% for the LPb and HPb groups, respectively; P-SH was lower by 8.2% and 13% for the LPb and HPb groups, respectively. Lead decreases levels of glutathione and protein thiol groups. Lead-induced oxidative stress contributes to the observed elevation of protein carbonyl groups. Besides, lead poisoning seems to be associated with hyperhomocysteinaemia, which may promote the development of atherosclerosis.

Influence of methionine and vitamin E on fluoride concentration in bones and teeth of rats exposed to sodium fluoride in drinking water.

Increased exposure to fluorine-containing compounds leads to accumulation of fluorides in hard tissues of bones and teeth, which may result in numerous skeletal and dental disorders. This study evaluates the influence of methionine and vitamin E on fluoride concentration in bones and teeth of rats subjected to long-term exposure to sodium fluoride in drinking water. The study was conducted in 30 3-month-old female Wistar FL rats. The animals were divided into five groups, six rats per group. The control group consisted of rats receiving only distilled water as drinking water. All other groups received NaF in the amount of 10 mg/kg of body mass/day in their drinking water. In addition, respective animal groups received: NaF + Met group--10 mg of methionine/kg of body mass/day, NaF + Met + E group--10 mg of methionine/kg of body mass/day and 3 mg of vitamin E (tocopheroli acetas)/rat/day and NaF + E group--3 mg of vitamin E/rat/day. Femoral bones and incisor teeth were collected for the study, and the fluoride concentration was determined using a fluoride ion-selective electrode. Fluoride concentration in both bones and teeth was found to be higher in the NaF and NaF + Met groups compared to the control group. In groups NaF + Met + E and NaF + E, the study material contained much lower fluoride concentration compared to the NaF group, while the effect was more prominent in the NaF + E group. The results of the studies indicate that methionine and vitamin E have opposite effects on accumulation of fluorides in hard tissue in rats. By stimulating fluoride accumulation, methionine reduces the adverse effect of fluorides on soft tissue, while vitamin E, which prevents excessive accumulation of fluorides in bones and teeth, protects these tissues from fluorosis. Therefore, it seems that combined application of both compounds would be optimal for the prevention of the adverse effects of chronic fluoride intoxication.

Influence of methionine on toxicity of fluoride in the liver of rats.

Oxidative stress is a common mechanism by which chemical toxicity can occur in the liver. The aim of the studies conducted has been to determine what influence the administration of methionine during intoxication with sodium fluoride may have upon the selected enzymes of the antioxidative system in rat liver. The experiment was carried out on Wistar FL rats (adult females) that, for 35 days, were administered distilled water, NaF, or NaF with methionine (doses: 10 mg NaF/kg bw/day, 10 mg Met/kg bw/day). The influence of administered NaF and Met was examined by analyzing the activity of the antioxidative enzymes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione transferase in the liver. The results suggest that fluoride reduces the efficiency of the enzymatic antioxidative system in the liver. Administration of methionine during intoxication with sodium fluoride does not have an advantageous influence upon the activity of superoxide dismutase, catalase, reductase, and glutathione transferase in the liver. The slight increase of the activity of glutathione peroxidase after administration of methionine may indicate its protective influence upon that enzyme.

Influence of methionine upon the activity of antioxidative enzymes in the kidney of rats exposed to sodium fluoride.

The intensified or uncontrolled formation of reactive oxygen species leads to disturbances of numerous biochemical processes. Among the factors inducing intensified free radical processes, fluoride ions are listed, among others. One of the organs most exposed to the toxic activity of fluorides is the kidney. In the study presented here, the influence of fluorine upon the activity of selected antioxidant enzymes in rat kidney has been examined, as well as antioxidant properties of methionine during intoxication with sodium fluoride. The experiment was carried out on Wistar FL rats (adult females) that for 35 days were administered water, NaF, NaF with methionine (doses: 10 mg NaF/kg bw/day, 10 mg Met/kg bw/day) . The influence of administered NaF and Met upon the antioxidative system in kidney was examined by analyzing the activity of the most important antioxidative enzymes (SOD, CAT, GPX, GR, GST). The studies carried out confirmed the disadvantageous effect of NaF upon the antioxidative system in rats (decrease in activity of antioxidative enzymes). Methionine increased the activity of antioxidative enzymes, most efficiently that of GPX, GR, and GST.

Influence of methionine upon the concentration of malondialdehyde in the tissues and blood of rats exposed to sodium fluoride.

The aim of the study has been to determine the influence upon the kidney, liver, and the blood prooxidative system, exercised by administration of methionine (Met), under conditions of oxidative stress induced by sodium fluoride (NaF).The experiment was carried out on Wistar FL rats (adult females) that, for 35 days, were administered distilled water, NaF or NaF with methionine (doses: 10 mg NaF/kg bw/day, 10 mg Met/kg bw/day). The influence of administered NaF and Met was examined by analyzing the concentration of malondialdehyde (MDA) in kidney, liver, erythrocytes, and blood plasma.The study confirmed the disadvantageous effect of NaF upon the antioxidative system in rats (an increase in the concentration of MDA).The administration of methionine reduced the process of lipid peroxidation (a decreased in the concentration of MDA). The best antioxidative properties have been demonstrated by methionine in rat liver.

Influence of fluoride on rat kidney antioxidant system: effects of methionine and vitamin E.

The aim of the study has been to determine and compare the influence upon the kidney antioxidative system, exercised by administration of vitamin E, and vitamin E in combination with methionine, under conditions of oxidative stress induced by sodium fluoride. The experiment was carried out on Wistar FL rats (adult males) that, for 35 days, were administered water, NaF, NaF with vitamin E, or vitamin E with methionine (doses: 10 mg NaF/kg of body mass/24 h, 3 mg vitamin E per 10 microl per rat for 24 h, 2 mg methionine per rat for 24 h). The influence of administered sodium fluoride and antioxidants upon the antioxidative system in kidney was examined by analyzing the concentration of malondialdehyde (MDA) and the activity of the most important antioxidative enzymes (SOD, total and both its isoenzymes, GPX, GST, GR, and CAT). The studies carried out confirmed the disadvantageous effect of the administered dose of NaF upon the antixodiative system in rats (increase in the concentration MDA, decrease activity of all antioxidative enzymes). The administration of vitamin E increased the activity of studied enzymes with the exception of glutathione reductase GR; it also reduced the processes of lipid peroxidation. It has been found that combined doses of vitamin E and methionine were most effective in inhibiting lipid peroxidation processes. The results confirmed the antioxidative properties of methionine.

[The effect of caffeine and sodium fluoride on fluoride concentration in serum and its content in teeth and bones of rats]. / Wplyw kofeiny i fluorku sodu na stiezenie fluorków w surowicy krwi i ich zawartosc w zebach i kosciach szczurów.

PURPOSE: The aim of this work was to determine the effect of sodium fluoride at a dose of 4.9 mg/kg b.w./24 h and caffeine at a dose of 3 mg/kg b.w./24 h on the concentration of fluoride in serum and its content in teeth and bones of rats. MATERIAL AND METHODS: The study was done in 18 male Sprague-Dawley rats. CONCLUSIONS: A negative effect of caffeine administered concurrently with sodium fluoride on teeth and bones of rats was demonstrated as reflected by a tendency to increased content of fluoride in bones and decreased content in teeth.