Role of histamine in short- and long-term effects of methamphetamine on the developing mouse brain

With the rise in methamphetamine (MA) use among women of childbearing age, the potential consequences of MA exposure to the developing brain for cognition in adulthood is a major concern. Histamine might mediate these MA effects. Following MA administration in neonatal mice, histamine levels in brain were elevated and the hypothalamic-pituitary-adrenal axis was activated. Co-administration of MA with the H3 receptor agonist immepip antagonized these effects. The effects of MA on histamine levels and on hypothalamic-pituitary-adrenal axis activation at P20 were more pronounced in female than male mice. These sex differences could have contributed to the increased susceptibility of female mice to the detrimental long-term cognitive effects of MA and the H3/H4 antagonist thioperamide. Following behavioral testing, mice neonatally treated with MA or thioperamide showed reduced levels of the dendritic marker microtubule-associated protein 2 in the CA3 region of the hippocampus and the enthorhinal cortex. This was not seen in mice neonatally treated with immepip and MA who did not show cognitive impairments, suggesting that these brain areas might be particularly important for the long-term effects of MA on cognitive function. These data support a role for histamine in the effects of MA on the developing brain.     

Hypothalamic neuronal histamine signaling in the estrogen deficiency-induced obesity

Menopause is one of the triggers that induce obesity. Estradiol (E2), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among E2, CRH, and histamine during the regulation of feeding behavior and obesity in rodents. Food intake was measured in rats after the treatment of E2, α-fluoromethyl histidine, a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine, or CRH antagonist. We measured food intake and body weight in wild-type mice or mice with targeted disruption of the histamine receptors (H1-R) knockout (H1KO mice). Furthermore, we investigated CRH content and histamine turnover in the hypothalamus after the E2 treatment or ovariectomy (OVX). We used immunohistochemical staining for estrogen receptors (ERs) in the histamine neurons. The E2-induced suppression of feeding was partially attenuated in rats pre-treated with α-fluoromethyl histidine or CRH antagonist and in H1KO mice. E2 treatment increased CRH content and histamine turnover in the hypothalamus. OVX increased food intake and body weight, and decreased CRH content and histamine turnover in the hypothalamus. In addition, E2 replacement reversed the OVX-induced changes in food intake and body weight in wild-type mice but not in H1KO mice. Immunohistochemical analysis revealed ERs were expressed on histamine neurons and western blotting analysis and pre-absorption study confirmed the specificity of ER antiserum we used. These results indicate that CRH and hypothalamic neuronal histamine mediate the suppressive effects of E2 on feeding behavior and body weight.     

On the role of histamine receptors in regulating pigmentary responses in Oreochromis mossambicus melanophores

Purpose: The present work was carried out to reveal the involvement of histamine receptors at the neuro-melanophore junction of teleost, Oreochromis mossambicus.

Methods: The isolated scale melanophores were assayed using the mean melanophore size index and their responses were recorded in presence of various concentrations of histamine along with H₁ and H₂ receptor specific agonists and antagonist and potentiator compound 48/80.

Results: Melanophores showed high sensitivity to histamine and its specific agonists. Histamine caused a dose-dependent pigment aggregation, whereas 2-(2-Pyridyl) ethylamine (PEA), a specific H₁R agonist also caused aggregation in a similar manner. Conversely, amthamine, a specific H₂R agonist resulted in pigment dispersion. The effects were antagonized by mepyramine; specific H₁R antagonist and ranitidine a specific H₂R antagonist.

Conclusion: It is concluded that O. mossambicus melanophores have both H₁ and H₂ receptors which mediate melanophore aggregation and dispersion respectively. Compound 48/80 augmented the melanin-aggregating and dispersing effects of PEA and amthamine. It is suggested that the effect of histamine is directly mediated through H1 and H2 receptors, whereas H1Rs may be predominantly involved in the aggregatory responses.     

Potentiation by histamine of synaptically mediated excitotoxicity in cultured hippocampal neurones: a possible role for mast cells

Excessive glutamatergic neurotransmission, particularly when mediated by the N:-methyl-D-aspartate (NMDA) subtype of glutamate receptor, is thought to underlie neuronal death in a number of neurological disorders. Histamine has been reported to potentiate NMDA receptor-mediated events under a variety of conditions. In the present study we have utilized primary hippocampal neurone cultures to investigate the effect of mast cell-derived, as well as exogenously applied, histamine on neurotoxicity evoked by excessive synaptic activity. Exposure of mature cultures for 15 min to an Mg(2+)-free/glycine-containing buffer to trigger synaptic transmission through NMDA receptors, caused a 30-35% neuronal loss over 24 h. When co-cultured with hippocampal neurones, activated mast cells increased excitotoxic injury to 60%, an effect that was abolished in the presence of histaminase. Similarly, addition of histamine during magnesium deprivation produced a concentration-dependent potentiation (+ 60%; EC(50) : 5 microM) of neuronal death which was inhibited by sodium channel blockers and NMDA receptor antagonists, although this effect did not involve known histamine receptors. The histamine effect was further potentiated by acidification of the culture medium. Cultures 'preconditioned' by sublethal (5 min) Mg(2+) deprivation exhibited less neuronal death than controls when exposed to a more severe insult. NMDA receptor activation and the extracellular regulated kinase cascade were required for preconditioning neuroprotection. The finding that histamine potentiates NMDA receptor-mediated excitotoxicity may have important implications for our understanding of conditions where enhanced glutamatergic neurotransmission is observed in conjunction with tissue acidification, such as cerebral ischaemia and epilepsy.     

佛波醇对大鼠大脑皮层突触体及人多形胶质瘤细胞株BT-325摄取谷氨酸的促进作用

采用大鼠大脑皮层突触体,人神经母细胞瘤细胞２株ＳＫ－Ｎ－ＳＨ及人多形胶质瘤细胞株ＢＴ－３２５作氚标谷氨酸高亲和摄取实验,探讨蛋白激酶Ｃ及蛋白激酶Ａ对于神经元性及胶质细胞性谷氨酸摄取的影响。     

Evidence of glutathione transporter in rat brain synaptosomal membrane vesicles

Glutathione (GSH) transport was studied in synaptosomal membrane vesicles (SMV) of rat cerebral cortex. The present study shows that GSH uptake into SMV occurs very quickly in a time-dependent manner into an osmotically active intravesicular space. The initial rate of transport followed Michealis-Menten saturation kinetics with a K_m 4.5±0.8 μM that shows a high affinity of the transporter for GSH. Therefore GSH uptake in SMV occurs by a mediated transport system which can be activated by either an inward gradient of cations, like Na⁺ or K⁺, or membrane depolarization. These results, together with those obtained by valinomycin-induced K⁺ diffusion potential, indicate that GSH synaptosomal transport is electrogenic by a negative charge transfer. The increase of GSH uptake measured by trans-stimulation experiments confirms a GSH bidirectional mediated transport which seems susceptible of modulation by changes in ionic fluxes and in the membrane potential. These results may indicate a possible involvement of this transporter in the role suggested for GSH in synaptic neurotransmission; also considering that GSH precursor of neuroactive aminoacids (glyeine, glutamate), may contribute to regulate their level in synapses. Finally, a GSH transporter in synaptosomes may contribute to maintaining the GSH homeostasis in cerebral cortex, where decreases of GSH levels have been related to susceptibility to neuropathologies.     

Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake

We examined the involvement of thyrotropin-releasing hormone (TRH) and TRH type 1 and 2 receptors (TRH-R1 and TRH-R2, respectively) in the regulation of hypothalamic neuronal histamine. Infusion of 100 nmol TRH into the rat third cerebroventricle (3vt) significantly decreased food intake (p < 0.05) compared to controls infused with phosphate- buffered saline. This TRH-induced suppression of food intake was attenuated partially in histamine-depleted rats pre-treated with alpha-fluoromethylhistidine (a specific suicide inhibitor of histidine decarboxylase) and in mice with targeted disruption of histamine H1 receptors. Infusion of TRH into the 3vt increased histamine turnover as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH, a major metabolite of neuronal histamine in the brain) in the tuberomammillary nucleus (TMN), the paraventricular nucleus, and the ventromedial hypothalamic nucleus in rats. In addition, TRH-induced decrease of food intake and increase of histamine turnover were in a dose-dependent manner. Microinfusion of TRH into the TMN increased t-MH content, histidine decarboxylase (HDC) activity and expression of HDC mRNA in the TMN. Immunohistochemical analysis revealed that TRH-R2, but not TRH-R1, was expressed within the cell bodies of histaminergic neurons in the TMN of rats. These results indicate that hypothalamic neuronal histamine mediates the TRH-induced suppression of feeding behavior.     

Up- and down-regulation of membrane receptors as possible mechanisms related to the antiulcer actions of milk in rat gastric mucosa

The effects of a cow's milk diet on receptor activity and histamine metabolism in gastric glands and mucosa isolated from adult rats were examined. The milk diet was associated with (1) a decreased mobilization of H₂ receptors by histamine and (2) an increased mobilization of PGE₂ (prostaglandin E₂) receptors in mucous cells (cytoprotective effect) and parietal cells (antiacid effect). These changes are not observed for the receptors reducing pentagastrin- and histamine-induced gastric acid secretion (pancreatic/enteroglucagons, somatostatin) and stimulating mucus, bicarbonate and pepsin secretions in the rat (secretin). Cimetidine produced a parallel displacement of the histamine dose-response curve, suggesting competitive inhibition between this classical H₂ receptor antagonist and histamine in the two experimental groups. Prostaglandins and other components in milk such as EGF (epidermal growth factor) and somatostatin might therefore protect gastric mucosa by a differential control of PGE₂ and histamine H₂ receptor activity eitherdirectly (PGE₂ in milk) orindirectly (inhibition of endogeneous histamine synthesis/release and stimulation of PGE-I synthesis/release).     

Characterization of reduced expression of glycine N-methyltransferase in cancerous hepatic tissues using two newly developed monoclonal antibodies

Glycine N-methyltransferase (GNMT) is a protein with multiple functions. Recently, two Italian siblings who had hepatomegaly and chronic elevation of serum transaminases were diagnosed to have GNMT deficiency caused by inherited compound heterozygosity of the GNMT gene with missence mutations. To evaluate the expression of GNMT in cell lines and tissues from hepatocellular carcinoma (HCC) patients, we produced two monoclonal antibodies (mAbs) 4-17 and 14-1 using two recombinant GNMT fusion proteins. M13 phage peptide display showed that the reactive epitopes of mAbs 4-17 and 14-1 were amino acid residues 11-15 and 272-276 of human GNMT, respectively. The dissociation constants of the binding between GNMT and mAbs were 1.7 x 10(-8) M for mAb 4-17 and 1.8 x 10(-9) M for mAb 14-1. Both mAbs can identify GNMT present in normal human and mouse liver tissues using Western blotting (WB) and immunohistochemical staining assay (IHC). In addition, WB with both mAbs showed that none of 2 hepatoblastoma and 5 HCC cell lines expressed GNMT. IHC demonstrated that 50% (13/26) of nontumorous liver tissues and 96% (24/25) of HCC tissues did not express GNMT. Therefore, the expression of GNMT was downregulated in human HCC.     

Reduced expressions of calmodulin genes and protein and reduced ability of calmodulin to activate plasma membrane Ca2+‐ATPase in the brain of protein undernourished rats: modulatory roles of selenium and zinc supplementation

The roles of protein undernutrition as well as selenium (Se) and zinc (Zn) supplementation on the ability of calmodulin (CaM) to activate erythrocyte ghost membrane (EGM) Ca²⁺‐ATPase and the calmodulin genes and protein expressions in rat's cortex and cerebellum were investigated. Rats on adequate protein diet and protein‐undernourished (PU) rats were fed with diet containing 16% and 5% casein, respectively, for a period of 10 weeks. The rats were then supplemented with Se and Zn at a concentration of 0.15 and 227 mg l⁻¹, respectively, in drinking water for 3 weeks. The results obtained from the study showed significant reductions in synaptosomal plasma membrane Ca²⁺‐ATPase (PMCA) activity, Ca²⁺/CaM activated EGM Ca²⁺ATPase activity and calmodulin genes and protein expressions in PU rats. Se or Zn supplementation improved the ability of Ca²⁺/CaM to activate EGM Ca²⁺‐ATPase and protein expressions. Se or Zn supplementation improved gene expression in the cerebellum but not in the cortex. Also, the activity of PMCA was significantly improved by Zn. In conclusion, it is postulated that Se and Zn might be beneficial antioxidants in protecting against neuronal dysfunction resulting from reduced level of calmodulin such as present in protein undernutrition. Copyright © 2016 John Wiley & Sons, Ltd.     

Lipid changes in the aged brain: effect on synaptic function and neuronal survival

As the brain ages, cognitive and motor performance decline. This decline is thought to be largely due to the accumulation of damaging products from normal oxidative metabolism and to the perturbation of general body homeostasis and brain-circulation separation. Despite this abundance of insults, the aged brain contains few dead neurons, suggesting that aging must be paralleled by triggering or enhancing neuronal survival mechanisms. Recent evidence points to the contribution of changes in the lipid composition of membranes to both age-dependent cognitive decline and robust neuronal survival. In this review, we describe and discuss the current understanding of the roles of lipids in neuronal aging, with special attention to their influence on membrane fusion, neurotransmitter receptor dynamics and survival/death signaling pathways.     

Enzymatic synthesis of N,N-dimethyl-sphingosine: demonstration of the sphingosine: N-methyltransferase in mouse brain

Based on our recent finding that N,N-dimethyl-D-erythro-sphingenine strongly inhibits protein kinase C (PK-C) whereas D-erythro-sphingenine produces only weak inhibition, we have studied the presence of N-methyltransferase responsible for conversion of sphingosine to its N,N-dimethyl derivative. The enzyme activity was detected in crude mouse brain tissue homogenate but was hardly detectable in liver homogenate, in which N-methylation of phosphatidylethanolamine (PE) is predominant.     

Effect of alpha-fluoromethylhistidine on the histamine content of the brain of W/Wv mice devoid of mast cells: turnover of brain histamine

In the brains of W/Wv mutant mice that have no mast cells, the histidine decarboxylase (HDC) level is as high as in the brain of congenic normal mice (+/+), but the histamine content is 53% of that of +/+ mice. The effects of alpha-fluoromethylhistidine (alpha-FMH) on the HDC activity and histamine content of the brain of W/Wv and +/+ mice were examined. In both strains, 30 min after i.p. injection of alpha-FMH the HDC activity of the brain had decreased to 10% of that in untreated mice. The histamine content decreased more gradually, and after 6 h about half of the control level remained in +/+ mice, whereas histamine had disappeared almost completely in W/Wv mice. It is concluded that the portion of the histamine content that was depleted by HDC inhibitor in a short time is derived from non-mast cells, probably neural cells. The half-life of histamine in the brain of W/Wv mice was estimated from the time-dependent decrease in the histamine content of the brain after administration of alpha-FMH: 48 min in the forebrain, 103 min in the midbrain, and 66 min in the hindbrain.     

Photoaffinity labelling of the serotinin carrier protein in platelets and brain synaptosomes

Azidoimipramine, a photoaffinity labelling reagent for the serotonin transport protein, was synthesized. This reagent, upon irradiation, binds covalently to brain synaptosomes preparation and to gel-filtered platelets. Two-dimensional SDS-polyacrylamide gel electrophoresis-isoelectric focussing and tritium fluorography analysis indicate that two synaptosomal proteins and four platelets proteins were labelled by [³H]azidoimipramine.     

Regional differences in the turnover of neuronal histamine in the rat brain

The turnover rate of histamine (HA) and the half-life of neuronal HA were estimated in 9 regions of the rat brain following pargyline-induced accumulation of tele-methylhistamine (t-MH). The turnover rate was the highest in the hypothalamus (108.7 ng/g/hr). The striatum also showed a high turnover rate (80.2 ng/g/hr) despite much lower levels of HA and t-MH, as compared with the levels in the hypothalamus. The turnover rate was relatively high in the thalamus, cerebral cortex, amygdala and midbrain, but it was very low in the cerebellum. t-MH accumulation in the spinal cord was nil. The HA levels were reduced to various degrees (from nil to less than 40% of the control) by (S)-alpha-fluoromethylhistidine, depending on the regions studied. The neuronal HA content of each brain region was subsequently estimated, and the half-life of neuronal HA in each region was calculated. The half-life of neuronal HA was the shortest (7.7 min) in the striatum, while it was long (about 50 min) in the hypothalamus and thalamus. Half-life values of about 20 min were obtained in other regions. These results show the high levels of histaminergic activity in some parts of the telencephalon, thalamus and midbrain as well as the hypothalamus.     

Reduced histamine levels and H3 receptor antagonist-induced histamine release in the amygdala of Apoe-/- mice

The histamine H(3) receptor is a constitutively active G protein-coupled receptor for the neurotransmitter histamine that serves a negative feedback function. A role for the histamine H(3) receptor has been suggested in neurodegenerative diseases, such as Parkinsons disease and Alzheimer's disease. Mice deficient in apolipoprotein E (apoE), a protein involved in development, regeneration, neurite outgrowth, and neuroprotection, show increased measures of anxiety and reduced sensitivity to effects of histamine H(3) receptor antagonists on measures of anxiety. In this study, we tested whether in mice lacking apoE (Apoe-/-) histamine levels and histamine release in brain areas involved in the regulation of anxiety are altered. H(3) receptor antagonist-induced histamine release was lower in the amygdala of Apoe-/- than wild-type mice. In contrast, there were no genotype differences in histamine release in the hypothalamus. Consistent with these data, histamine immunohistochemistry revealed lower total and synaptic histamine levels in the central nucleus of the amygdala of Apoe-/- than wild-type mice. Such changes were not seen in the hypothalamus, hippocampus, or cortex. In Apoe-/- mice, chronically decreased histamine levels and reduced histamine release in the amygdala might contribute to increased measures of anxiety.     

S100, a brain-specific protein: Localization and possible role in the snail nervous system

Immunofluorescence techniques were used to show that S100 is present on the surface of neuronal and glial membranes of Helix pomatia in vitro. By the method of rocket immunoelectrophoresis of aqueous, Trition, and n-pentanol extracts of snail nervous tissue, S100 was demonstrated to be mainly in the membrane fraction. Anti-S100 antiserum inhibited the electrical activity of identified neurons, pointing to a relationship of this protein with ionic channels of the excitable membrane. The effect of anti-S100 antiserum on the membrane was potential dependent and controlled by the Ca²⁺ concentration.     

Localization and role of sulfoglycolipid immobilizing protein 1 on the mouse sperm head

Sulfoglycolipid immobilizing protein 1 (SLIP1) is an evolutionally conserved sperm head plasma membrane protein (M_r = 68 kDa) that binds to sulfogalactosylglycerolipid (SGG), the major sulfoglycolipid present in mammalian sperm. The purpose of this study was to characterize the initial localization and the immunoaggregated relocalization of SLIP1 on the mouse sperm head. Direct immunofluorescence (DF) of live sperm using FITC-antiSLIP1 Fab fragments and FITC-antiSLIP1 IgG indicated that SLIP1 was present in the postacrosomal region of the sperm head, although the intensity of immunostaining by FITC-antiSLIP1 IgG was greatest at the border between the postacrosomal region and the acrosome. Unlike that observed with FITC-antiSLIP1 Fab, DF using FITC-antiSLIP1 IgG indicated that SLIP1 was also present in the anterior tip of the sperm head convex ridge. Results from electron microscopic studies, using antiSLIP1 IgG followed by protein A-gold on live mouse sperm, were similar to the DF findings. In contrast, indirect immunofluorescence (IIF) of live mouse sperm using antiSLIP1 IgG and FITC-secondary antibody IgG detected SLIP1 in the sperm head convex ridge only. The IIF and DF results strongly suggest that these bivalent antibodies could induce the sperm antigen relocalization on live sperm heads. SLIP1 redistribution may be dependent on availability of excess SGG, the SLIP1 binding ligand, based on the observation that purified exogenous biotinylated SLIP1 bound to live mouse sperm at both the postacrosomal and convex ridge regions of the mouse sperm head. Immunoaggregation induced by the primary antiSLIP1 IgG or antiSLIP1 Fab with secondary antibody IgG did not cause the acrosome reaction, suggesting that SLIP1 is not involved in sperm signal transduction. Furthermore, postacrosomal SLIP1 was shown to be involved in zona binding, since sperm pretreated with antiSLIP1 Fab fragments (100 μg/ml) bound to the egg zona pellucida in vitro at ∼35% of control levels. Mol. Reprod. Dev. 48:518–528, 1997. © 1997 Wiley-Liss, Inc.