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ABSTRACT: The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients' plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.
Brain Behavior and Immunity 05/2011; 25(8):1576-81. · 4.72 Impact Factor
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A R Van Gool,
R Verkerk,
D Fekkes,
S Sleijfer,
M Bannink,
W H J Kruit,
B van der Holt, S Scharpé,
A M M Eggermont,
G Stoter,
M W Hengeveld
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ABSTRACT: Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.
Journal of Interferon & Cytokine Research 06/2008; 28(5):283-6. · 3.06 Impact Factor
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W Zhai,
M Cardell,
I De Meester,
K Augustyns,
S Hillinger,
I Inci,
S Arni,
W Jungraithmayr, S Scharpé,
W Weder,
S Korom
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ABSTRACT: CD26/Dipeptidyl peptidase (DPP) IV is an integral membrane protein of lymphocytes that modulates the activities of chemokines, interleukins, and neuropeptides. We investigated the effect of enzymatic DPP IV inhibition on ischemia/reperfusion injury after extended ischemia prior to transplantation.
We used a syngeneic rat (Lewis) orthotopic left lung transplantation model. In the control group (group I), donor lungs were flushed and preserved in Perfadex for 18 hours at 4 degrees C, then transplanted and reperfused for 2 hours. Group II donor lungs were perfused with and stored in Perfadex +25mol/L AB192 (bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate), a small molecular weight DPP IV inhibitor. After 2-hour reperfusion, we measured blood gas, peak airway pressure, and thiobarbituric acid reactive substances.
Grafts from group II versus group I showed a significantly increased oxygenation capacity (II: 298.4 +/- 87.6 mm Hg vs 120.9 +/- 48.0, P < .01), lower peak airway pressure (11.8 +/- 0.9 mm Hg vs 16.0 +/- 1.4, P < .01), and less lipid peroxidation (9.3 +/- 2.0 micromol/L vs 13.8 +/- 1.8, P < .01).
Inhibition of intragraft DPP IV enzymatic activity significantly reduced ischemia/reperfusion-associated pulmonary injury, allowing for successful transplantation after 18 hours of ischemia.
Transplantation Proceedings 12/2006; 38(10):3369-71. · 1.00 Impact Factor
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ABSTRACT: Studies show that administration of interferon (IFN)-alpha causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-alpha-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-alpha treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood-brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-alpha treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-alpha-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.
Molecular Psychiatry 07/2005; 10(6):538-44. · 13.67 Impact Factor
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A R Van Gool,
H H Van Ojik,
W H J Kruit,
P G H Mulder,
D Fekkes,
M Bannink, S Scharpé,
G Stoter,
A M M Eggermont,
M Maes,
R Verkerk
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ABSTRACT: Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.
Journal of Interferon & Cytokine Research 08/2004; 24(7):411-5. · 3.06 Impact Factor
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S Korom,
I De Meester,
E Maas,
A Stein,
S Wilker,
F Jung,
R Weimer,
M D Brendel,
W Ernst,
S Friemann,
R Linder,
H Grimm,
W Padberg, S Scharpé,
J W Kupiec-Weglinski,
K Schwemmle
Transplantation Proceedings 09/2002; 34(5):1753-4. · 1.00 Impact Factor
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ABSTRACT: To test the hypothesis that the direct thrombin inhibitor, melagatran is able to inhibit local pro-carboxypeptidase U (proCPU) activation that occurs during thrombolytic treatment, t-PA alone, or in combination with melagatran, was given to dogs with a coronary artery thrombosis. Blood samples from the great cardiac vein and aorta were collected at baseline, during thrombus formation, throughout the t-PA+/-melagatran infusion and during the patency period, for analysis of CPU activity using a novel assay. A higher CPU activity in venous compared to arterial blood (V-A difference) indicates CPU activation in coronary vessels. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Dogs (n = 26) were randomized to receive either 1) t-PA, 1 mg/kg as an intravenous 20-min infusion; 2) t-PA as in group 1, +melagatran bolus, 0.3 mg/kg, followed by a 3-h infusion (0.15 mg/kg per h); 3) sham-operated but no coronary thrombus, and administered t-PA as for Group 1. All groups had similar baseline characteristics. Significant increases in CPU activity were observed in Groups 1 and 2 during thrombus formation, with V-A differences of 5.5 and 4.5 U/L, respectively. No significant V-A difference was observed in the sham-operated group. CPU activity increased in Group 1 during the t-PA infusion (V-A difference 15.9 U/L), whereas the V-A difference in Group 2 decreased to 2.6 U/L following melagatran treatment. These results demonstrate that melagatran attenuates generation of CPU in the coronary circulation. The mechanism is probably indirect, via inhibition of thrombin-mediated activation of proCPU.
Thrombosis and Haemostasis 05/2002; 87(4):557-62. · 5.04 Impact Factor
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ABSTRACT: Dipeptidyl-peptidase IV (DPPIV/CD26) metabolizes neuropeptides regulating insulin secretion. We studied the in vitro steady-state kinetics of DPPIV/CD26-mediated truncation of vasoactive intestinal peptide (VIP), pituitary adenylyl cyclase-activating peptide (PACAP27 and PACAP38), gastrin-releasing peptide (GRP) and neuropeptide Y (NPY). DPPIV/CD26 sequentially cleaves off two dipeptides of VIP, PACAP27, PACAP38 and GRP. GRP situates between the best DPPIV/CD26 substrates reported, comparable to NPY. Surprisingly, the C-terminal extension of PACAP38, distant from the scissile bond, improves both PACAP38 binding and turnover. Therefore, residues remote from the scissile bond can modulate DPPIV/CD26 substrate selectivity as well as residues flanking it.
FEBS Letters 12/2001; 507(3):327-30. · 3.54 Impact Factor
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ABSTRACT: Chemokines coordinate many aspects of leukocyte migration. As chemoattractants they play an important role in the innate and acquired immune response. There is good experimental evidence that N-terminal truncation by secreted or cell surface proteases is a way of modulating chemokine action. The localization of CD26/dipeptidyl peptidase IV on cell surfaces and in biological fluids, its primary specificity, and the type of naturally occurring truncated chemokines are consistent with such a function. We determined the steady-state catalytic parameters for a relevant selection of chemokines (CCL3b, CCL5, CCL11, CCL22, CXCL9, CXCL10, CXCL11, and CXCL12) previously reported to alter their chemotactic behavior due to CD26/dipeptidyl peptidase IV-catalyzed truncation. The results reveal a striking selectivity for stromal cell-derived factor-1alpha (CXCL12) and macrophage-derived chemokine (CCL22). The kinetic parameters support the hypothesis that CD26/dipeptidyl peptidase IV contributes to the degradation of certain chemokines in vivo. The data not only provide insight into the selectivity of the enzyme for specific chemokines, but they also contribute to the general understanding of CD26/dipeptidyl peptidase IV secondary substrate specificity.
Journal of Biological Chemistry 09/2001; 276(32):29839-45. · 4.77 Impact Factor
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ABSTRACT: There is now evidence that the availability of plasma tryptophan is decreased during pregnancy and the puerperium and also in patients with major depression and inflammation. The aims of the present study were to examine: (i) the effects of pregnancy and delivery on plasma tryptophan and the amino acids known to compete for the same cerebral uptake mechanism (CAAs), valine, leucine, tyrosine, phenylalanine and isoleucine; (ii) the relationships between the availability of plasma tryptophan and postpartum depression or anxiety; and (iii) the relationships between the availability of plasma tryptophan to the brain and inflammatory markers, such as serum interleukin-6 (IL-6), interleukin-1 receptor-antagonist (IL-1RA) and the leukaemia inhibitory factor receptor (LIF-R).
The above variables were measured in 13 healthy non-pregnant and in 98 pregnant women 3 to 6 days before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the state version of Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS).
Plasma tryptophan and the tryptophan/CAA ratio were significantly lower at the end of term and after delivery than in the plasma of non-pregnant, healthy women. The tryptophan/CAA ratio was significantly lower in the early puerperium than at the end of term. There were no significant relationships between the availability of plasma tryptophan and either post-partum depression or changes in the STAI or ZDS scores in the early puerperium. The changes in the tryptophan/CAA ratio from the end of term to the early puerperium were significantly and inversely related to serum IL-6, IL-IRA and LIF-R.
The results show that the reduction in the availability of plasma tryptophan from the end of term to the early puerperium is related to immune activation; and that the lowered availability of plasma tryptophan is not related either to depressive or anxiety symptoms in the early puerperium or to post-partum depression ensuing some months later.
Psychological Medicine 08/2001; 31(5):847-58. · 6.16 Impact Factor
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ABSTRACT: In 1988, Hendricks et al. first reported on the presence of carboxypeptidase U (U refers to the unstable nature of the enzyme) in human serum. One decade later, the importance of carboxypeptidase U (CPU) in the regulation of fibrin clot dissolution is well documented. CPU circulates in plasma as an inactive zymogen, proCPU, that is converted to its active form during coagulation and fibrinolysis. CPU cleaves off C-terminal lysine residues exposed on fibrin partially degraded by the action of plasmin. Because these C-terminal lysine residues are important for upregulating the fibrinolytic rate, CPU thus slows down fibrinolysis.
Clinical and Applied Thrombosis/Hemostasis 05/2001; 7(2):93-101. · 1.33 Impact Factor
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ABSTRACT: Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
Verhandelingen - Koninklijke Academie voor Geneeskunde van België 02/2001; 63(1):5-32; discussion 32-3.
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ABSTRACT: There is some evidence that hormonal and serotonergic alterations may play a role in the pathophysiology of paraphilias. The aims of the present study were to examine: 1) baseline plasma cortisol, plasma prolactin, and body temperature; and 2) cortisol, prolactin, body temperature, as well as behavioral responses to meta-chlorophenylpiperazine (mCPP) and placebo in pedophiles and normal men. Pedophiles showed significantly lower baseline plasma cortisol and prolactin concentrations and a higher body temperature than normal volunteers. The mCPP-induced cortisol responses were significantly greater in pedophiles than in normal volunteers. In normal volunteers, mCPP-induced a hyperthermic response, whereas in pedophiles no such response was observed. mCPP induced different behavioral responses in pedophiles than in normal men. In pedophiles, but not in normal men, mCPP increased the sensations "feeling dizzy, " "restless," and "strange" and decreased the sensation "feeling hungry". The results suggest that there are several serotonergic disturbances in pedophiles. It is hypothesized that the results are compatible with a decreased activity of the serotonergic presynaptic neuron and a 5-HT2 postsynaptic receptor hyperresponsivity.
Neuropsychopharmacology 02/2001; 24(1):37-46. · 7.99 Impact Factor
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ABSTRACT: The aims of the present study were to examine serotonergic markers, i.e. [3H]paroxetine binding characteristics and the availability of plasma tryptophan, the precursor of serotonin (5-HT), and the plasma concentrations of the branched chain amino acids (BCAAs), valine, leucine and isoleucine, in fibromyalgia. The [3H]paroxetine binding characteristics, B(max) and K(d) values, and tryptophan and the competing amino acids (CAA), known to compete for the same cerebral uptake mechanism (i.e. valine, leucine, isoleucine, phenylalanine and tyrosine), were determined in fibromyalgia patients and normal controls. There were no significant differences in the [3H]paroxetine binding characteristics (B(max) and K(d)) between fibromyalgia and control subjects. There were no significant differences in plasma tryptophan or the tryptophan/CAA ratio between fibromyalgia patients and normal controls. In the fibromyalgia patients, there were no significant correlations between [3H]paroxetine binding characteristics or the availability of tryptophan and myalgic or depressive symptoms. Patients with fibromyalgia had significantly lower plasma concentrations of the three BCAAs (valine, leucine and isoleucine) and phenylalanine than normal controls. It is hypothesized that the relative deficiency in the BCAAs may play a role in the pathophysiology of fibromyalgia, since the BCAAs supply energy to the muscle and regulate protein synthesis in the muscles. A supplemental trial with BCAAs in fibromyalgia appears to be justified.
Psychiatry Research 01/2001; 97(1):11-20. · 2.52 Impact Factor
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ABSTRACT: The importance of carboxypeptidase U as a novel regulator of the fibrinolytic rate has attracted a lot of interest recently. In the present work, an ELISA was developed using polyclonal antibodies raised against recombinant proCPU, expressed in DON cells. The assay determines the antigen concentration of the zymogen of carboxypeptidase U, procarboxypeptidase U, in human citrated plasma or EDTA plasma. No interference is observed with plasma carboxypeptidase N. The assay is very reproducible (within-run: 4.6% CV, between-run: 6.8% CV). In a group of 479 healthy individuals the mean proCPU antigen concentration is 13.4 microg/ml (SD 2.5 microg/ml). A good correlation is found with the functional procarboxypeptidase U assay described earlier (r = 0.82, p < 0.0001) (Schatteman K, Goossens F, Scharpé S, Neels H, Hendriks D Clin Chem 1999: 45: 807-813). The significant correlation between the proCPU antigen concentration and the 50% clot lysis time stresses its importance as a player in fibrinolysis control.
Thrombosis and Haemostasis 01/2001; 85(1):12-7. · 5.04 Impact Factor
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ABSTRACT: Dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) is a serine type protease with an important modulatory activity on a number of chemokines, neuropeptides and peptide hormones. It is also known as CD26 or adenosine deaminase (ADA; EC 3.5.4.4) binding protein. DPPIV has been demonstrated on the plasmamembranes of T cells and activated natural killer or B cells as well as on a number of endothelial and differentiated epithelial cells. A soluble form of CD26/DPPIV has been described in serum. Over the past few years, several related enzymes with similar dipeptidyl peptidase activity have been discovered, raising questions on the molecular origin(s) of serum dipeptidyl peptidase activity. Among them attractin, the human orthologue of the mouse mahogany protein, was postulated to be responsible for the majority of the DPPIV-like activity in serum. Using ADA-affinity chromatography, it is shown here that 95% of the serum dipeptidyl peptidase activity is associated with a protein with ADA-binding properties. The natural protein was purified in milligram quantities, allowing molecular characterization (N-terminal sequence, glycosylation type, CD-spectrum, pH and thermal stability) and comparison with CD26/DPPIV from other sources. The purified serum enzyme was confirmed as CD26.
European Journal of Biochemistry 10/2000; 267(17):5608-13. · 3.58 Impact Factor
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ABSTRACT: Procarboxypeptidase U (proCPU) is the plasma precursor of carboxypeptidase U (CPU, carboxypeptidase R. plasma carboxypeptidase B or activated thrombin-activatable fibrinolysis inhibitor, TAFIa). CPU removes C-terminal lysine residues that act as plasminogen binding sites from partially degraded fibrin, thereby down-regulating plasminogen activation and fibrinolysis. The present study was carried out as a pilot study to examine whether the plasma proCPU concentration is related to the presence of coronary artery disease (CAD) and/or to levels of established risk indicators for CAD, in a case-control study of 110 men requiring coronary artery bypass grafting (CABG) because of stable angina pectoris. The preoperative plasma proCPU level in the CABG patients was significantly higher than in population-based controls (1029 +/- 154 vs. 974 +/- 140 U/L, p <0.05). In addition, in a subset of the patients (n = 31 ) the proCPU concentration, which was significantly lower on the third postoperative day (-17 +/- 10%), had increased significantly on the sixth day (+14 +/- 12%) after surgery, compared with the preoperative level. In both patients and controls, proCPU concentration was strongly and positively associated with factor VII amidolytic activity and protein C activity, suggesting a common mechanism modulating the plasma levels of these proteins. Otherwise, statistically significant correlations with proCPU were group-specific. In the patients, proCPU correlated significantly with plasma fibrinogen and protein S. In the controls, proCPU correlated significantly with concentrations of cholesterol in plasma. VLDL and LDL. In addition, proCPU correlated significantly with C-reactive protein and haptoglobin levels in the controls only, indicating that also inflammatory mechanisms are involved in the regulation of plasma proCPU. These results suggest that a mechanism exists by which fibrinolytic function is impaired in a manner that is likely to result in more stable fibrin deposits and increase the risk of precocious CAD as well as early occlusion of venous bypass grafts.
Thrombosis and Haemostasis 09/2000; 84(3):364-8. · 5.04 Impact Factor
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ABSTRACT: Serotonin (5-HT) is a neurotransmitter and an immune modulator. In vitro, antidepressants with a serotonergic mode of action have, at concentrations within the therapeutical range, negative immunoregulatory effects, i.e., they increase the production rate of interleukin-10 (IL-10), a negative immunoregulatory cytokine. We have hypothesized that part of these effects may be explained by the serotonergic activities of antidepressants on immunocytes. This study was carried out to examine the effects of 5-HT, p-chlorophenylalanine (PCPA), a 5-HT depleting agent, flesinoxan (a 5-HT1A agonist), m-chlorophenylpiperazine (mCPP; a 5-HT2A/2C agonist), and ritanserin (a 5-HT2A/2C antagonist) on the production rate of interferon-gamma (IFNgamma), a proinflammatory cytokine, and IL-10 by whole blood stimulated with polyclonal activators. The IFNgamma/IL-10 production ratio was computed, since this ratio reflects the pro- versus anti-inflammatory capacity of cultured whole blood. We found that: 1) 5-HT, 150 ng/mL, 1.5 microg/mL, and 15 microg/mL significantly decreased the IFNgamma/IL-10 ratio; 2) PCPA (5 microM) significantly suppressed the production of IFNgamma and IL-10; 3) flesinoxan (15 ng/mL; 1.5 microg/mL) had no significant effects on the production of the above cytokines; and 4) mCPP (2.7 microg/mL) and ritanserin (5.0 microg/mL) suppressed the IFNgamma/IL-10 ratio. It is concluded that intracellular 5-HT may be necessary for an optimal synthesis of IFNgamma and IL-10, and that extracellular 5-HT concentrations at or above serum values may suppress the production of the proinflammatory cytokine IFNgamma. The negative immunoregulatory effects of antidepressive drugs are probably not related to their serotonergic activities.
Neuropsychopharmacology 08/2000; 23(1):89-98. · 7.99 Impact Factor
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ABSTRACT: Many studies have demonstrated that major depression is related to an activation of the inflammatory response system (IRS) with an increased production of proinflammatory cytokines. It has been shown that tricyclic antidepressants and serotonin reuptake inhibitors suppress the activation of the IRS in depression and have negative immunoregulatory effects in vitro. Little is known on the immune effects of moclobemide, a reversible monoamine oxidase A inhibitor.
We examined, in nine normal volunteers, the in vitro effects of moclobemide on the production of interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), IL-10 and the IL-1 receptor antagonist (IL-1RA) by diluted whole blood stimulated or not with lipopolysaccharide (LPS)+phytohemagglutinin (PHA).
Moclobemide 10(-3) and 10(-5) M significantly suppressed the unstimulated production of TNFalpha and IL-8, and significantly enhanced the stimulated-production of IL-10. The production of IL-6, IL-1RA and IFNgamma was not significantly affected either in the unstimulated or stimulated conditions.
Moclobemide has negative immunoregulatory capacities through inhibition of the production of proinflammatory cytokines, i.e. TNFalpha and IL-8, and through enhancement of the production of IL-10, an anti-inflammatory cytokine.
Journal of Affective Disorders 05/2000; 58(1):69-74. · 3.52 Impact Factor
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Advances in experimental medicine and biology 02/2000; 477:67-87. · 1.09 Impact Factor
