Neuronal storage of histamine in the brain and tele-methylimidazoleacetic acid excretion in portocaval shunted rats.

Rats with portocaval anastomosis (PCA), an animal model of hepatic encephalopathy (HE), have very high brain histamine concentrations. Our previous studies based on a biochemical approach indicated histamine accumulation in the neuronal compartment. In this study, immunohistochemical evidence is presented which further supports the amine localization in histaminergic neurons. These neurons become pathological in appearance with cisternae frequently seen along histaminergic fibres in many brain areas, including the hypothalamus, amygdala, substantia nigra and cerebral cortex. Such formations were not observed in sham-operated animals. The neuronal deposition is predominant, and unique for histamine. It serves as a mechanism to counterbalance excessive brain neurotransmitter formation evoked by PCA. However, there are other mechanisms. The data provided here show that there is also a significant increase in histamine catabolism in the shunted rats, as reflected by both the higher brain N-tele-methylhistamine (t-MeHA) concentration and urinary excretion of N-tele-methylimidazoleacetic acid (t-MelmAA), a major brain histamine end product. The stomach, in addition to the brain, is a site of enhanced histamine synthesis in portocavally shunted subjects. After gastrectomy or food deprivation to eliminate the contribution of the stomach, shunted rats excrete significantly more t-MelmAA, implying the role of the CNS. This last finding suggests that under strictly defined conditions, namely in parenterally fed HE patients with abnormal plasma L-histidine, the measurement of urinary t-MelmAA might provide valuable information concerning putative brain histaminergic activity.

Liver regeneration attenuates increased voluntary alcohol intake evoked by the liver damage.

Liver dysfunction induced in Wistar rats either surgically (by construction of portocaval anastomosis) or chemically (by chronic administration of thioacetamide) led to increased voluntary alcohol intake. Alcohol preference could be attenuated by liver regeneration that was triggered by a two-thirds hepatectomy done on cirrhotic rats. The brain serotonin system was activated in portocaval anastomosis rats and unchanged in thioacetamide-treated rats, thus suggesting that serotonin is not likely to be implicated in the mechanism(s) underlying development of alcohol preference in these rats. Also, tetrahydro-beta-carboline could possibly be excluded from consideration. Neither change in the brain concentration or distribution of tetrahydrobetacarboline after long-term treatment with thioacetamide could be found.

Effect of pargyline on brain N-tele-methylhistamine in portocaval-shunted rats: relation to amine neurotransmitters.

HPLC determination of histamine, serotonin, dopamine, and noradrenaline in the brain tissue of rats with portocaval anastomoses (PCA) has revealed a selective increase in histamine concentration. In the posterior hypothalamus, the steady-state level of the amine metabolites showed an inverse pattern; N-tele-methylhistamine (t-MeHA), as estimated by gas chromatography-mass spectrometry, was not changed significantly by portocaval shunting, whereas 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid were more than doubled. Interestingly, the net increase in t-MeHA concentration in response to pargyline (80 mg/kg i.p.) was almost the same for PCA and sham-operated rats. This implies that the great enhancement of the histamine level in this area might be a consequence of the persistent stimulation of its synthesis and the unchanged activity of histaminergic neurons. In the rest of the brain, on the other hand, the steady-state level of t-MeHA was higher after PCA (3.8-fold), as were the levels of 5-HIAA and homovanillic acid. Surprisingly, t-MeHA remained unchanged after monoamine oxidase blockade. Of the pargyline-induced alterations in the concentrations of indoles and catechols, the most pronounced were those in the serotonin level; serotonin was elevated more than twofold in hypothalamus and more than 12-fold in the rest of the brain, with a concomitant 80% decrease in 5-HIAA. The dopamine and, to a much smaller extent, noradrenaline levels were also increased, and the levels of homovanillic acid and 3,4-dihydroxyphenylacetic acid fell below the detection limit. The study suggests that at least two different mechanisms operate in the brains of PCA rats to counteract the excessive synthesis of neuromediators, e.g., increased deposition and increased metabolism.

The FAD dependent amine oxidases in relation to developmental state of enterocyte.

Epithelial cells from bovine and guinea pig small intestines contain monoamine and polyamine oxidases with MAO-A preponderance at any maturational stage. For either species, Km values for 5HT and N1acetylspermine remain throughout cellular maturation on the same levels, whereas the Vmax values do not. For serotonin, the dividing crypt cells showed in cow lower and in guinea pig higher Vmax than the mature cells; for N1acetylspermine, mature cells, independently of species, showed lower Vmax.

Histamine: its metabolism and localization in mammary gland.

1. Mammary gland of mouse (Mus musculus), rat (Rattus rattus), guinea pig (Cavia porcellus), cow (Bos taurus) and pig (Sus scrofa) contains different but always high concentrations of histamine. 2. Generally, the tissue histamine is localized in mast cells, although non-mast cell histamine immunoreactivity is also present in mammary glands of the mouse, cow and pig. No histamine immunoreactive nerves could be detected. 3. Mammary glands are able to synthesize and inactivate histamine; the activity of specific histidine decarboxylase and at least one of the catabolizing enzyme could be demonstrated. 4. Histamine fulfils basic criteria for being involved in physiological function of mammary glands.

The influence of Tolpa Peat Preparation (TPP) on rat liver regeneration.

The effect of Tolpa peat preparation (TPP) on the regenerative response has been examined in rats submitted to two thirds hepatectomy. The ornithine decarboxylase activity, spermidine and histamine levels, DNA and RNA content, RNA/DNA ratio and the mass of restituted liver were used to test the intensity of the regenerative processes. The action of TPP is dual: a short-term application of TPP at a dose of 20 mg/kg/day causes an inhibition of the ornithine decarboxylase activity, the decrease in spermidine formation, the levels of DNA and RNA, and liver restitution. The multiple application of TPP, on the other hand, results in a stimulation of ornithine decarboxylase, the increase in spermidine and histamine as well as RNA and DNA levels in regenerating liver; concomitantly, the liver mass tends to increase in TPP treated groups. TPP might exert its effects, at least partially, by interfering with polyamine biosynthesis.

Investigations on allergogenic properties of Tolpa Peat Preparation.

The ability of Tolpa Peat Preparation (TPP) to induce or enhance an allergic sensitization was tested on mice and guinea pigs. The levels of IgE antibody in the mouse sera and IgG1 as well as IgE antibody levels in guinea pig sera were evaluated by PCA (Passive Cutaneous Anaphylaxis) tests. TPP adsorbed on aluminium hydroxide gel (alum) and introduced into BALB/c mice by several subcutaneous injections was unable to stimulate the noticeable anti-TPP IgE antibody response. TPP introduced together with ovalbumin (OA) into the mice in the course of immunization with OA did not enhance anti-OA IgE antibody response. TPP adsorbed on alum and injected subcutaneously into guinea pigs was unable to induce noticeable IgG1a, IgG1b and IgE antibody response, and mast cells obtained from lung and mesentery of these animals did not release histamine when challenged with TPP in vitro at 37 degrees C. In conclusion, our results show that under the experimental conditions used in the present experiments TPP was unable to induce or enhance an allergic sensitization of mice and guinea pigs.

Influence of Tolpa Peat Preparation on the IgE-induced anaphylactic reactions in mice.

The ability of Tolpa Peat Preparation (TPP) to affect anaphylactic sensitization and mast cell secretory function was tested in BALB/c mice treated with TPP orally for 12 days. TPP in the doses of 20 and 50 mg/kg/day reduced histamine release from mouse peritoneal mast cells challenged with anti-IgE or concanavalin A in vitro. The treatment of mice with TPP from day 1 to day 12 of immunization with Ovalbumin (OA) absorbed on aluminium hydroxide gel resulted in a decrease of antigen-induced histamine release from mast cells of these mice in vitro and in decreased IgE antibody level in their sera. TPP introduced into OA-immunized mice showing developed IgE antibody response was less effective in decreasing anaphylactic histamine release from mast cells of these mice. In all experiments low doses of TPP used for oral treatment were more effective than high doses in inhibiting anaphylactic events in the mice.

Decreased histamine content and metabolism in mammary cancer tissue from C3H mice.

Histamine (HA) level and its metabolism in adenocarcinoma mammae, spontaneously growing cancer in C3H mice, were examined in relation to the type of tumor, intensity of tumor vascularization and the presence or absence of a secretory function. Histamine concentration being in mammary gland one of the highest among mammalian organs (418 nmol/g) was decreased by 90% in tumor (34 nmol/g). Similarly, histidine decarboxylase (HDC) activity dropped from approximately 7.6 pmol/min/g in normal gland to an undetectable level in adenocarcinoma mammae. Of the two main HA degrading enzymes, namely, diamine oxidase and histamine N-methyl-transferase (HMT), only HMT could be detected in mammary gland, either healthy or neoplastic, and its activity was about 5-fold lower in tumor than in the control tissue (1 nmol/g/min vs. 5.2 nmol/g/min). The pattern of changes in histaminergic parameters evoked by the tumor was similar irrespective of the morphological type it represented, characteristics of its vascular bed or whether or not it showed secretory activity.

The immunomodulating preparation Ukrain does not induce anaphylactic sensitization in mice and guinea pigs.

The ability of Chelidonium majus L. alkaloids derivative Ukrain to induce an anaphylactic sensitization was tested on mice and guinea pigs. The levels of IgE antibody in the mouse sera, and IgG1a, IgG1b as well as IgE antibody levels in guinea pig sera, were evaluated by passive cutaneous anaphylaxis (PCA) tests. Ukrain alone or adsorbed on aluminium hydroxide gel (alum) introduced into BALB/c mice in several subcutaneous injections was unable to stimulate measurable anti-Ukrain IgE antibody response. Moreover, Ukrain introduced together with ovalbumin (OA) into mice in the course of immunization with OA induced lower anti-OA antibody response as compared to the response induced by OA alone. Ukrain adsorbed on alum and injected subcutaneously into guinea pigs did not induce measurable IgG1a, IgG1b and IgE antibody response. The present results suggest that the immunomodulating preparation Ukrain could be therapeutically safe at least as far its inability to induce anaphylaxis is concerned.

Liver damage, voluntary alcohol intake and brain histamine.

Liver dysfunction induced by protocaval anastomosis (PCA) in the rat is associated with a great reduction of hepatic alcohol and aldehyde dehydrogenase activities. Despite this, PCA rats voluntarily drank more alcohol than unoperated rats. When subjected to forced alcohol consumption, shunted rats maintained their exaggerated voluntary alcohol intake whereas unoperated rats developed aversion to alcohol. Hypothalamic levels of both histamine and histidine were very high in PCA rats. When these rats were chronically exposed to alcohol, there was a slight decrease in hypothalamic histidine concentration and consequently a lower histamine content. Chronic exposure to alcohol did not, however, influence hypothalamic tissue levels of histamine or histidine in unoperated rats. In both groups, chronic alcohol treatment exerted a stimulatory effect on hepatic alcohol metabolizing enzymes.

Histamine in C3H/W mice carrying spontaneous tumors of the mammary gland.

Adenocarcinoma mammae, a spontaneously growing mammary cancer in C3H/W mice, contrary to many transplanted tumors does not evoke any rise in histamine level either in the tumor or in distant tissues. On the other hand, the histamine level is reduced by 90% in the tumor in comparison with the healthy gland. This seems to be a consequence of the fall of histidine decarboxylase activity to below a detectable level. There is also a significant reduction in histamine N-methyltransferase activity to one-fifth of the control level. The healthy mammary gland contains a high concentration of histamine and catabolizes it exclusively through the methylation pathway.