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Background: Histamine is widely used as a pharmacological tool for the evaluation of airway responsiveness. Nevertheless, undesirable and contradictory effects have been described after histamine provocation tests. In previous evaluations of airway responsiveness in a guinea pig asthma model, the control groups consistently showed high neutrophil counts in bronchoalveolar lavage fluid (BALF) immediately after the histamine challenge. The changes in cytokine and chemokine levels in guinea pig lung associated with histamine induced-neutrophilia are described in this paper. Methods: Immediately and 24 h after histamine challenge, airway wall and BALF eosinophil and neutrophil counts as well as lung cytokines (IL-5, IL-10, IL-17A, TNFα and TGFβ) and chemokines (CCL11 and CXCL8) levels were evaluated. Results: Histamine inhalation generated an all-or-none bronchial response, and the dose inducing airway obstruction was similar in all guinea pigs. Immediate increases in neutrophil counts in airway wall and BALF and in IL-5, IL-10 and IL-17A levels in the lung homogenate were observed after histamine challenge. Significant correlations were found between neutrophil counts from airway wall and IL-5, IL-10 and IL-17A levels in the lung homogenate. Conclusions: Histamine inhalation induced rapid neutrophil LBA and airway wall infiltration that was not associated with CXCL8 expression but with a Th2 and Th17 cytokines that probably are involved in the recruitment and activation of neutrophils.
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Abstract: Platelets llave serotonin (5-HT) uptake and storage mechanisms similar to those from neurons. In addition, they represent nearly 99% of blood 5-HT concentration. For these characteristics, platelets are considered useful biomarkers of the serotonergic synaptic neurotransmission, particularly in psychiatric disturbances such as depression. However, most studies which have evaluated platelet 5-HT concentrations in depression have not shown similar findings. It has been suggested that changes in plasma tryptophan (TRP) concentrations might modify 5-HT concentration in the brain, as well as in platelets. Likewise, decreased plasma concentrations of TRP have been found in depressed patients, and the selective 5-HT reuptake inhibitors (SSRIs) induce changes in platelet 5-HT concentration. Considering the controversy surrounding platelet 5-HT concentrations in depressed patients, and the fact that blood 5-HT and TRP have not been studied in the Mexican population, we decided to study 5-HT and tryptophan concentrations in blood and platelets from depressed and control Mexican subjects to evaluate a possible correlation with the severity of depression. The effect of fluoxetine and citalopram treatment on blood and platelet 5-HT and TRP concentrations in depressed patients was also studied. Material and methods Depressed patients The patients of this study were carefully selected and evaluated. Scales based on semi-structured interviews were applied (MINI and SCID-II) by clinical investigators to reduce any possible bias in patient selection. The influence of the seasonal variability on the 5-HT or TRP blood concentrations was controlled by pairing depressed patients and healthy subjects according to age, gender and, in the case of women, menstrual cycle phase. Patients with a complete remission of depression symptoms (defined as a score not higher than 5 points in the Hamilton's scale, and lower than 7 points in Beck's scale) were asked for a blood sample to measure platelet and blood concentrations of 5-HT and TRP. The patients were weighted before the treatment and after their improvement. Control subjects The control group was integrated by 30 healthy subjects, 24 women and 6 men, with an average age of 32.3 ± 10.8 years. Participants were recruited from the overall Mexican population, interviewed by a psychiatrist, and evaluated with the structured interview MINI and the SCID-II, all these to discard any psychiatric diagnose. None of them had received any pharmacological treatment during the three weeks prior to the study. Control and depressed women were paired according to their menstrual cycle phase. All participants received a detailed explanation of the study, and those who voluntarily accepted the stipulations signed an informed consent document. Control and patient subjects were clinically examined and studied with routine laboratory tests (blood count, blood chemistry, urinalysis, and thyroid function test). Blood sample procedures 5-HT and TRP measurements in total blood preparation were carried out according to the method described by Anderson, and were quantified by high performance liquid chromatography (HPLC). Statistical analysis The differences were statistically determined through an analysis of variance (ANOVA), with the assistance of the SPSS 12.00 (Statistical Software by SPPS Inc.). Results Results from laboratory tests, such as blood count, blood chemistry, thyroid function (T3, T4 and TSH) and urinalysis were normal in depressed subjects, as well as in healthy volunteers. Platelet number, blood 5-HT concentration, platelet content of 5-HT, and blood tryptophan concentration showed no significant differences in depressed patients in comparison to control subjects. 5-HT values in blood and platelet were significantly lower than the initial concentrations in patients after antidepressant treatment. Discussion and conclusions Discrepancies between our study and those found in the literature can be explained with three different approaches: ethnical, physiological, and methodological, as is further discussed. The significant decrease produced by the antidepressant treatment in blood and platelet serotonin concentration may be a consequence of the action of SSRIs, due to a 5-HT diminished uptake by the platelet. Considering our results, we conclude that: Blood and platelet 5-HT concentrations were not different between depressed patients and healthy volunteers. Blood TRP concentrations were not different between depressed patients and healthy volunteers. SSRIs (fluoxetine or citalopram) used in the treatment of depressed patients induced a significant decrease in blood and platelet content of 5-HT, and had no effect in TRP concentrations. Based on these results, neither blood/platelet 5-HT nor blood tryptophan concentrations seem to be good biological markers of depressive patients status. However, 5-HT, but not tryp-tophan, might be a reference point for pharmacological treatment effect.
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Abstract: Nowadays there are increasing number of studies to support the crucial role of monoamines in depressive disorders. Among them are studies such as long-term treatment of antidepressants whose mechanism of action regulates monoamine metabolism, monoamine receptor density and post-mortem studies. An acute increase in monoamine concentration at the synaptic cleft might induce desensitization of brain auto- and hetero-receptors which explains the therapeutic antidepressive response. This has been proved by monoamine depletion studies in which an antidepressant effect or a patient relapse has been observed. Likewise, the antidepressive therapeutic response occurs earlier when auto-receptors are pharmacologically blocked at nervous and somatodendritic terminals. In the first part of this review, post-mortem studies related with the serotoninergic system were analyzed, as well as the usefulness of measuring serotonin, triptophan, and serotonin metabolite levels in different biological fluids of depressed patients. In this second part, alterations in platelet transporter and serotonin receptors are discussed as platelet is considered a neural serotoninergic model. Platelets are capable of storing and releasing serotonin in a similar manner as serotoninergic synaptosomes. Thus, platelets and serotoninergic synaptic terminals share biochemical and morphological properties. Serotonin transporter in platelets of depressed patients Due to the difficulty to obtain human brain samples and disagreements in the post-mortem studies, platelets have been suggested as a peripheral model to study neural serotonin uptake. The model is supported by the fact that platelet properties are similar to those of neuronal serotoninergic synaptic terminals. Serotonin studies in platelets have been useful in clinical aspects such as depressive disturbances. Radioligand studies in platelets from untreated depressed patients have shown a decrease in [H]-imipramine binding sites, compared to the binding in platelets from control subjects. Since that decrease has been consistently confirmed in studies on affective subjects, it has been proposed as a specific biomarker of depressed patients. Nevertheless, some researchers have not found similar results, and no explanation of the variability in the density of [H]-imipramine binding sites has been proposed. Serotonin receptor changes in depressed patients The hypothesis on receptor adaptative changes proposes that there is a depletion of monoaminergic neurotransmitters in depressed subjects which induces a compensatory regulation in the number and/or function of receptors. To explore this different techniques as the following have been developed: • Techniques to evaluate receptor density and affinity, including post-mortem radioligand binding to serotonin receptors in brain tissue and in platelets from depressed patients. • Techniques to evaluate receptor regulation and sensitivity by using neuroendocrine tests described below. Somatodendritic 5HT 1A autoreceptor dysfunction in depressive disorders Dysfunction of presynaptic somatodendritic 5HTja autoreceptors has been found in behavioral changes related to anxiety, depression and alcoholism. Neuroendocrine tests after the administration of 5-HT1a agonists have been used as an index of 5-HTta receptor function. It seems that azapirodecanediones increase plasmatic concentrations of prolactin, somatotropin, and adrenocortico-tropin; they also seem to decrease body temperature. In depressed patients, the hypothermia response, following presynaptic 5-HTta receptor stimulation, and the neuroendocrine response, following hypothalamus postsynaptic 5-HTta receptor stimulation, were both diminished. These findings suggest a desensitization or down-regulation of pre- and post-synaptic 5-HTja receptors in depressed patients. Platelet 5-HT 2A receptors in depressed patients Density and affinity Most radioligand studies have found an increase of platelet 5-HT2a receptors either in major depression patients or in attempted suicide patients. However, Rosel et al. studied platelets from depressed patients, finding an increment in the 5-HT2a platelet receptors affinity for [H]-ketanserin, but not in the receptors density. Functional capacity The evaluation of receptor function and sensitivity in platelets is performed after serotonin stimulation by using neuroendocrine tests and some other functional tests, such as platelet aggregation, morphological changes, quantification of intracellular calcium, and second messengers quantification. Despite being widely used, neuroendocrine tests are not completely reliable because they could be influenced by factors such as: stress on the hypothalamus-hypophysis axis, the lack of stereo-selective agonists and antagonists for different subtype serotonin receptors, and the effect of the drugs on other neurotransmitter systems. Other methodological aspects, such as: population heterogeneity, small samples, lack of variable control (i.e. age, sex, doses, diet, menstrual cycle), and placebo effects, are limitations to the neuroendocrine tests related to a single neurotransmitter system (serotonin). Results from platelet functional studies are contradictory as well. Platelet aggregation assays in depressed patients suggested a down-regulation of 5-HT2A receptors, compared to platelets from healthy subjects. However, some other studies have found no differences. Other platelet function responses mediated by 5-HT2A receptors, such as morphology changes, intracellular calcium, and phosphatidyl inositol hydrolysis, suggest a receptor up-regulation or hypersensitivity in depressed patients. Despite some disagreement among the results of platelet 5-HT2A receptor studies in depressed patients, most of them have reported an increase in 5-HT2A receptors density in these patients. However, suicidal behavior is clearly correlated to such an increase. Similar results have been observed in most post-mortem studies reporting an increase of 5-HT2A receptors in the prefrontal cortex. Protein synthesis and mRNA for 5-HT2A receptors are increased in prefrontal cortex and hippocampus in adolescent and adult suicide victims. These findings suggest that changes in the brain serotonergic system are related to depressive states and suicidal behavior. Human brain imaging techniques as well as molecular genetics studies may be additional tools to support the understanding of the neurobiology of depressive states, and their treatment.
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Summary According to Spitzer et al., depression is a mood disorder characterized by sadness and accompanied by other symptoms such as irritability, anxiety, significant weight/appetite loss or gain, and feelings of guilt, worthlessness and hopelessness. Depressed patients are unable to accomplish everyday activities and may develop thoughts of death or suicide. Different neurotransmitters have been involved in the pathogenesis of depression; among them are noradrenaline, dopamine, gamma-aminobutyric acid, neuropeptides such as vasopressin and somatostatin, and endogenous opioids. However, serotonin (5-HT) has been the most studied and is suggested to play a central, but not exclusive, role in depression. This review analyzes studies which have involved serotonin as the vulnerable biochemical factor in depression. Postmortem studies Postmortem studies and 5-HT and 5-hydroxy-indolacetic acid quantification Many researchers have reported a decrease in 5-HT or its metabolite 5-hydroxy-indolacetic acid (5-HIAA) concentration in the brain stem of suicidal people. However, results are inconsistent since in other cerebral regions, such as the hypothalamus, cingulate and frontal cortex, no 5-HT or 5-HIAA concentrations have been found. Validity of postmortem results is limited by methodological issues as postmortem interval length, age of subjects, lack of assessment of nutritional status of suicide victims, drug abuse, medication, and differences in psychiatric diagnosis. Serotonin transporter and post-mortem studies Serotonin transporters are localized in cell presynaptic membranes in raphe and serotoninergic terminals projected to brain cortex. Radioligand studies have shown the occurrence of high affinity binding sites for [3H]-imipramine in human brain. Because of their localization in serotoninergic terminals and their likely participation in depression pathology, these binding sites have been suggested to be depression biomarkers. Early studies reported a decrease in [3H]-imipramine binding to prefrontal cortex in suicide victims with previous depression, as well as in occipital cortex and hippocampus in depressed patients who died of natural causes. These findings have been confirmed by other compound studies including [3H]-citalopram which has been identified as a more selective ligand for the serotonin transporter. A review by Purselle and Nemeroff of studies correlating depression, serotonin and suicide behavior found ambiguous data. These were likely due to methodological deficiencies such as a small sample size, deficient pairing criteria for control and treated groups, differences in radioligands, as well as disregarding comorbidity. These differences limit validation, comparison and interpretation of study results. Serotonin receptors and postmortem studies 5-HT 1A receptors. A decrease in 5-HT1A receptor density has been reported in suicidal depressed victims in the hippocampus, an important brain area for cognitive function. However, this receptor is highly sensitive to antidepressant treatment, which makes its determination rather ambiguous. On the other hand, no significant difference in brain cortex 5-HT1A receptors has been found between non-suicidal and suicidal subjects. 5-HT 1D receptors affinity has been reported to be decreased in depressed patients. 5-HT 2 receptors. Several researchers have observed an increase in postsynaptic 5-HT2 receptors in the frontal cortex and amygdala in suicidal depressed victims and depressed patients with no pharmacological treatment. An increase in 5-HT2A receptors has been reported in prefrontal cortex of suicidal adolescents, as well as higher levels of mRNA codifying for these receptors in prefrontal cortex and hippocampus. Tryptophan, serotonin, melatonin and 5-hydroxy-indolacetic acid in biological fluids Tryptophan in cerebrospinal fluid Findings on tryptophan levels in cerebrospinal fluid are controversial, for both normal and low levels have been found in depressed patients. Tryptophan in plasma Using the hypothesis of a decreased tryptophan availability to explain a low serotoninergic central activity in depressed patients does not stand due to different findings in levels of plasma-free tryptophan. Lower, normal and even higher levels of free tryptophan have been reported. Tryptophan availability might be influenced by neutral amino acids competing to cross the blood-brain barrier. Brain tryptophan levels might be modified if the free tryptophan/neutral amino acids ratio is reduced. It has been observed that depressed patients receiving antidepressants experienced a depressive relapse after receiving a low-tryptophan diet and returned to the remission state on returning to a regular food intake. Pharmacokinetic and pharmacodynamic factors might play a role in tryptophan availability in some depressed patients. Serotonin in cerebrospinal fluid Serotonin levels in cerebrospinal fluid are very low; this difficult carrying out studies in depressed patients. Serotonin in platelets Methodological and clinical criteria may explain the controversial results on platelet serotonin levels, which have found to be increased, decreased or unchanged. Serotonin in blood As platelet serotonin content includes 99% blood serotonin, serotonin blood levels might reflect brain serotonin content. After using fluvoxamine, a specific serotonin-reuptake inhibitor, the serotonin concentration in whole-blood preparation of patients was strongly reduced. After treatment with an unspecific mono-amine oxidase inhibitor, serotonin content was increased. Determination of 5-HT in whole blood preparation of patients treated with fluvoxamine might indicate a measure of drug compliance. Serotonin in plasma A significant decrease in plasma serotonin levels has been reported in depressed patients. Melatonin in plasma The melatonin synthesis use serotonine as building blocka. Melatonin have an important role in depression. It has been proposed that depressive states are a consequence of an inappropriate melatonin secretion. Therefore low plasmatic melatonin levels may be used as a biological marker for some types of depression. 5-HIAA in cerebrospinal fluid and plasma 5-HIAA, the major metabolite of 5-HT in plasma, has been suggested as a depression biomarker since cerebrospinal fluid 5-HIAA levels have found to be decreased in depressed patients. On the other hand, plasma 5-HIAA levels from untreated depressed patients were found to be significantly negatively correlated with severity of depression, despite the fact that the origin of plasma 5-HIAA is largely peripheral. 5-HIAA in urine Studies concerning urine 5-HIAA levels have been inconclusive in depression, likely due to the 5-HIAA urinary level variations from one day to another. Furthermore, the major fraction of 5-HIAA in blood as an intestinal precedence, therefore, blood 5-HIAA levels may not correlate with cerebral levels. Conclusion The serotoninergic system seems to be the neurotransmission system whose variations may explain every clinical manifestation in depressed patients. However, interpretation of measurements of tryptophan, serotonin, and its metabolites in biological fluids as an index of brain serotonin availability and function is difficult to achieve, mainly due to methodological discrepancies.