Depression,glucose tolerance,peripheral glucose uptake and their alterations under the influence of anti-depressive drugs of the hydrazine type

Summary In a group of depressive patients a study was made of the influence of isocarboxazid on hunger sensations, on the peripheral glucose uptake and on the mobilization of glucose from liver glycogen. The group was symptomatologically homogeneous: all patients showed the symptoms of the vital depressive syndrome. We established the following. 1. In the group of patients showing improvement upon isocarboxazid medication (group A), the glucose value prior to treatment was significantly lower than that in the group of patients refractory to this drug (group B). During medication the glucose value showed a distinct increase, and after treatment it remained at a normal level. 2. Group B showed a tendency corresponding to that in group A, but this just escaped attaining the level of statistical significance. 3. Mayer's glucostatic theory of hunger regulation was not corroborated. 4. Isocarboxazid does not demonstrably inhibit intrahepatic glycogenolysis.In a previous study we demonstrated that the therapeutic effect of anti-depressive hydrazines is accompanied by an increase in glucose tolerance. It is assumed that the increased extrahepatic glucose uptake now observed is responsible for this phenomenon. Finally it is concluded that (in view of the composition of groups A and B) metabolic factors must be considered in addition to the psychopathological features when using anti-depressive hydrazines.This work was aided by grants from the Netherlands Organization for Pure Research (Z.W.O.).     

Spin adduct formation from lipophilic EMPO-derived spin traps with various oxygen- and carbon-centered radicals

Free radicals are involved in the onset of many diseases, therefore the availability of adequate spin traps is crucial to the identification and localization of free radical formation in biological systems. In recent studies several hydrophilic compounds of 2-ethoxycarbonyl-2-methyl-pyrroline-N-oxide (EMPO) have been found to form rather stable superoxide spin adducts with half-lives up to twenty minutes at physiological pH. This is a major improvement over DMPO (t_1/2 = ca. 45 s), and even over DEPMPO (t_1/2 = ca. 14 min), the best commercially available spin trap for the unambiguous detection of superoxide radicals. In order to allow the detection of superoxide and also other radicals in lipid environment a series of more lipophilic derivatives of EMPO was synthesized and their structure unambiguously characterized by ¹H and ¹³C NMR spectroscopy. In this way, six different compounds with a n-butyl group in position 5 and either an ethoxy- (EBPO), propoxy- (PBPO), iso-propoxy- (iPBPO), butoxy- (BBPO), sec-butoxy- (sBBPO) or tert-butoxycarbonyl group (tBBPO) in position 5 of the pyrroline ring were obtained and fully analytically characterized (NMR, IR). The stability of the superoxide adducts of all investigated spin traps were comparable with EMPO (t_1/2 = ca. 8 min), except for the two compounds bearing an additional methyl group in position 3 or 4 of the pyrroline ring, 5-butyl-5-ethoxycarbonyl-3-methyl-pyrroline-N-oxide (BEMPO-3) and 5-butyl-5-ethoxycarbonyl-4-methyl-pyrroline-N-oxide (BEMPO-4), of which the superoxide adducts were stable for more than 30 min. Spin adducts of other carbon- and oxygen-centered radicals were also investigated.     

Very stable superoxide radical adducts of 5-ethoxycarbonyl- 3,5-dimethyl-pyrroline N-oxide (3,5-EDPO) and its derivatives

Oxygen radicals are involved in the onset of many diseases. Adequate spin traps are required for identification and localisation of free radical formation in biological systems. Superoxide spin adducts with half-lives up to 20 min at physiological pH have recently been reported to be formed from derivatives of the spin trap 5-ethoxycarbonyl-5-methyl-1-pyrroline N-oxide (EMPO). This is a major improvement over DMPO (t(1/2) ca. 45 s), and even DEPMPO (t(1/2) ca. 14 min). In this study, an additional methyl group was introduced into position 3 or 4 of the pyrroline ring which greatly increases the stability of the respective superoxide spin adducts. In addition, the ethoxy group of EMPO was exchanged by either a propoxy- or an iso-propoxy group in order to test the influence of increasing lipophilic properties of the investigated spin traps. The structure of all compounds was confirmed by (1)H and (13)C-NMR with full signal assignment. In comparison with EMPO (t(1/2) ca. 8 min) or DEPMPO (t(1/2) ca. 14 min), the superoxide adducts of all novel spin traps were considerably higher (t(1/2) ca. 12-55 min). In addition, various other spin adducts obtained from oxygen-centered as well as carbon-centered radicals (e.g. derived from methanol or linoleic acid hydroperoxide) were also detected.     

Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver

Interindividual variability in hepatic canalicular transporter expression might predispose to the development of hepatic disorders such as acquired forms of intrahepatic cholestasis. We therefore investigated expression patterns of bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4), multidrug resistance associated protein 2 (MRP2, ABCC2) and multidrug resistance protein 1 (MDR1, ABCB1) in healthy liver tissue of a white population. Protein expression levels were correlated with specific single nucleotide polymorphisms (SNPs) in the corresponding transporter genes. Hepatic protein expression levels from 110 individuals undergoing liver resection were assessed by Western blot analysis of liver plasma membranes enriched in canalicular marker enzymes. Each individual was genotyped for the following synonymous (s) and nonsynonymous (ns) SNPs: ABCB11: (ns:1457T>C and 2155A>G), ABCB4: (ns:3826A>G) and ABCC2 (ns:1286G>A,3600T>A and 4581G>A) and ABCB1 (ns:2677G>T/A and s:3435C>T). Transporter expression followed unimodal distribution. However, of all tested individuals 30% exhibited a high expression and 32% a low or very low expression phenotype for at least one of the four investigated transport proteins. Transporter expression levels did not correlate with age, sex, underlying liver disease, or presurgery medication. However, low BSEP expression was associated with the 1457C-allele in ABCB11 (P = .167) and high MRP2 expression was significantly correlated with the 3600A and 4581A ABCC2 variants (P = .006). In conclusion, the results demonstrate a considerable interindividual variability of canalicular transporter expression in normal liver. Furthermore, data suggest a polymorphic transporter expression pattern, which might constitute a risk factor for the development of acquired forms of cholestatic liver diseases.     

Germline mutations of the MSR1 gene in prostate cancer families from Germany

The MSR1 gene at 8p22 has been suggested as a candidate gene for hereditary prostate cancer because germline variants have been found to be associated with the disease. Aside from a single nonsense mutation (R293X) that was found repeatedly at low frequencies in several samples, little evidence has been gained by follow-up studies to confirm the gene's relevance for prostate cancer. Prompted by reasonable support for a linkage to 8p22, we sought to determine the mutation spectrum of MSR1 in our family sample. Screening of 139 probands (representing 139 prostate cancer families) revealed 15 novel and a total of 20 sequence variants within the 10 coding exons and their intronic proximities. Aside from the known mutation c.877C>T (R293X) present in two of our families, we identified a second nonsense allele (c.251C>G; S84X) and a splice-site mutation (c.818-1G>A) that results in mRNA instability (each in a single pedigree). The novel missense alleles were c.703C>T (H235Y), c.856C>T (P286S), c.905C>T (P302L), c.1193C>G (A398G), and c.1289A>G (K430R). Of the eight variants that affect the encoded protein (splice site, nonsense, and missense), only R293X as well as the polymorphism c.823C>G (P275A) were additionally present at remarkable frequencies in further samples of sporadic prostate cancer and controls. Of note, carriers of R293X were equally frequent in 367 sporadic prostate cancer cases (1.9%) and in 197 controls (2.0%). To our knowledge, our study is the first to demonstrate further loss of function variants of MSR1 apart from R293X. Nevertheless, the low frequencies of deleterious alleles, in addition to an apparently moderate penetrance, does not support MSR1 as a major susceptibility gene in this family sample.     

Oxygen sensors in hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV.     

Low zone tolerance induced by systemic application of allergens inhibits Tc1-mediated skin inflammation

BACKGROUND: The induction of tolerance may be a promising target of strategies aimed at preventing harmful allergic diseases. Low zone tolerance (LZT), induced by epicutaneous application of low doses of contact allergens, inhibits the development of T(C)1-mediated contact hypersensitivity (CHS). OBJECTIVE: We evaluated the effect of systemic (oral, intravenous) administration of low amounts of haptens on specific immune reactions and tolerance induction. METHODS: By using the mouse model of LZT, we analyzed immune reactions in vivo (skin inflammation) and T-cell responses in vitro after oral, intravenous, or epicutaneous application of low amounts of the contact allergen 2,4,6-trinitro-1-chlorobenzene (TNCB). RESULTS: Subimmunogenic doses of TNCB applied orally and intravenously induced a significant tolerance reaction in vivo comparable to epicutaneously tolerized mice, indicating that LZT is a systemically mediated tolerance reaction. In vitro analysis in all models of LZT revealed the generation of IL-10 secreting, regulatory CD4+ T cells that were absolutely required for the development of hapten-specific CD8+ T(C)2 cells. Adoptive transfer experiments identified CD8+ T(C)2 cells as effector T cells of LZT inhibiting the development of CHS-promoting T(C)1 cells and consequently the manifestation of CHS. These suppressor CD8+ T(C)2 cells were found as well in skin-draining as in mesenteric lymph nodes and in the spleen of tolerized animals independent of the route of tolerization. CONCLUSION: These data indicate that systemic uptake and presentation of small amounts of haptens (eg, contact allergens, drugs, metals) induce the development of LZT and thus prevent inappropriate activation of the immune system and protect from allergic diseases. CLINICAL IMPLICATIONS: These findings will be of particular importance because tolerance induction by protocols applying subimmunogenic, low amounts of haptens may be used as tools for immunotherapy in allergic and autoimmune diseases.     

Cerebrovascular reactivity following administration of mirtazapine in healthy probands--a randomized, placebo controlled double-blind clinical study

INTRODUCTION: Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is important for maintaining constant cerebral blood flow. A reduced CVR increases the risk of stroke. We recently found that CVR was reduced in patients with depression. This might contribute to the higher risk of stroke that has been found in subjects suffering from depression. The characterization of pathophysiological conditions in the cerebral circulation requires the knowledge of influencing factors on CVR. We therefore investigated the influence that antidepressant administration might have on CVR in humans. METHODS: We investigated CVR in 48 healthy men before and after a 10-day application of either mirtazapine or placebo. CVR was determined by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial Doppler ultrasound. RESULTS: There was no significant group-difference of CVR after the treatment trial compared to baseline. DISCUSSION: Mirtazapine does not seem to have an influence on CVR, or any impact on CVR might have been quickly limited by a cerebral autoregulatory response.