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1.
Transl Psychiatry ; 4: e479, 2014 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-25386956

RESUMEN

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/sangre , Melatonina/sangre , Serotonina/análogos & derivados , Serotonina/sangre , Transducción de Señal/fisiología , Adolescente , Adulto , Biomarcadores/sangre , Niño , Trastornos Generalizados del Desarrollo Infantil/genética , Femenino , Humanos , Masculino , Padres , Hermanos
2.
Neuroscience ; 238: 148-58, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23454367

RESUMEN

The stability and efficacy of neuronal circuits are achieved through a detailed balance between pyramidal cell and interneuron activities. Interestingly, the neocortical excitatory-inhibitory (E-I) balance is actively maintained at the soma of Layer 5 pyramidal neurons which receive 20% of excitation and 80% of inhibition after dendritic integration, and this is not affected by changes in synaptic strength. To infer the role of serotonergic neuromodulation on the activity-dependent maintenance of the E-I balance, we performed continuous voltage clamp measurements of stimulation-locked conductance dynamics in Layer 5 pyramidal neurons before and after long-term potentiation (LTP) induction, together with chronic or acute manipulation of serotonin function. When a theta-burst stimulation was applied in Layer 2/3 of 5-HT depleted cortical slices (after in vivo treatment with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (pCPA)), or after in vitro perfusion of the potent 5-HT1A receptor antagonist WAY-100,635, we observed a persistent shift of the ratio between excitation and inhibition toward more inhibition. This was due to a strong LTP of inhibition co-aligned with a weak LTP of excitation, whereas the same protocol caused a similar potentiation of excitatory and inhibitory inputs when applied in control slices. In contrast, neither excitatory nor inhibitory postsynaptic currents were potentiated when LTP protocols were delivered in the presence of either the selective serotonin reuptake inhibitor citalopram or the 5-HT1A receptor agonist 8-OH-DPAT. This is the first demonstration that serotonergic neuromodulation is crucial for the maintenance of the neocortical E-I balance during high-frequency regimes.


Asunto(s)
Potenciación a Largo Plazo/fisiología , Células Piramidales/fisiología , Serotonina/metabolismo , Sinapsis/fisiología , Corteza Visual/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Citalopram/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Células Piramidales/efectos de los fármacos , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinapsis/efectos de los fármacos , Corteza Visual/efectos de los fármacos
3.
Eur Respir J ; 32(2): 426-36, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18321937

RESUMEN

Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung. In the present study, the role of serotonin in lung fibrosis was investigated using the bleomycin mouse model. Serotonin concentrations in lung homogenates increased significantly over the time course of bleomycin-induced fibrosis, with a maximum at day seven. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin treatment, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors by ketanserin and 5-HT2B receptors by SB215505 reduced bleomycin-induced lung fibrosis, as demonstrated by reduced lung collagen content and reduced procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an antifibrotic environment by decreasing the lung mRNA levels of transforming growth factor-beta1, connective growth factor and plasminogen activator inhibitor-1 mRNA, but had minimal effects on lung inflammation as assessed by bronchoalveolar lavage cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples. In conclusion, the present study showed involvement of serotonin in the pathophysiology of bleomycin-induced lung fibrosis in mice and identified it as a potential therapeutic target in lung fibrotic disorders.


Asunto(s)
Bleomicina/toxicidad , Fibroblastos/metabolismo , Pulmón/patología , Fibrosis Pulmonar/patología , Antagonistas de la Serotonina/farmacología , Animales , Antibióticos Antineoplásicos/farmacología , Fibroblastos/efectos de los fármacos , Humanos , Ketanserina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Fibrosis Pulmonar/inducido químicamente , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1/metabolismo , Receptores de Serotonina 5-HT2/metabolismo
4.
J Pharmacol Exp Ther ; 317(2): 724-31, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16461587

RESUMEN

A correlation between high plasma serotonin levels and total pulmonary resistance was reported in more than 80% of pulmonary hypertensive patients. When submitted to chronic hypoxia (10% O(2) for more than 3 weeks), wild-type mice develop lung vascular remodeling and pulmonary hypertension. We previously reported that, in contrast, the development of these hypoxia-dependent alterations is totally abolished in mice with permanent (genetic) or transient (pharmacologic) inactivation of the serotonin 5-hydroxytryptamine (5-HT)(2B) receptor. In the present study, we asked whether 5-HT(2B) receptors could be involved in the control of plasma serotonin levels. Further investigating the chronic hypoxic mouse model of pulmonary hypertension, we first show that in wild-type mice, plasma serotonin levels and 5-HT(2B) receptors expression were significantly increased after chronic exposure to hypoxia. This increase appeared before significant changes in remodeling factors could be detected and persisted when the pathology was established. Conversely, in mice with either genetically or pharmacologically inactive 5-HT(2B) receptors, plasma serotonin levels were not modified by chronic hypoxia. We then confirmed that 5-HT(2B) receptors can control plasma serotonin levels by providing in vivo evidence that an acute agonist stimulation of 5-HT(2B) receptor triggers a transient increase in plasma serotonin that is serotonin transporter dependent and blocked by 5-HT(2B) receptor-selective antagonist or genetic ablation. Our data support the notion that a 5-HT(2B) receptor-dependent regulation of serotonin uptake is implicated in the control of plasma serotonin levels.


Asunto(s)
Hipertensión Pulmonar/sangre , Hipoxia/sangre , Receptor de Serotonina 5-HT2B/fisiología , Serotonina/sangre , Animales , Femenino , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Masculino , Ratones , Ratones Mutantes , Arteria Pulmonar/metabolismo , Receptor de Serotonina 5-HT2B/genética , Antagonistas del Receptor de Serotonina 5-HT2
5.
Nat Med ; 8(10): 1129-35, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12244304

RESUMEN

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.


Asunto(s)
Hipertensión Pulmonar/metabolismo , Receptores de Serotonina/metabolismo , Animales , Presión Sanguínea , División Celular , ADN/biosíntesis , Dexfenfluramina/metabolismo , Dexfenfluramina/farmacología , Modelos Animales de Enfermedad , Femenino , Humanos , Hipertensión Pulmonar/patología , Hipoxia/fisiopatología , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Técnicas de Cultivo de Órganos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Pirimidinas/farmacología , Receptor de Serotonina 5-HT2B , Receptores de Serotonina/genética , Serotonina/metabolismo , Antagonistas de la Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Vasoconstricción
6.
J Neurochem ; 82(3): 615-24, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12153485

RESUMEN

We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist of the thiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (approximately 20 mg/kg/day) attenuated the MPTP-induced glial activation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARgamma expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARgamma-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.


Asunto(s)
Trastornos Parkinsonianos/prevención & control , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazoles/farmacología , Tiazolidinedionas , Factores de Transcripción/agonistas , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Administración Oral , Animales , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Inmunohistoquímica , Antígeno de Macrófago-1/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroglía/efectos de los fármacos , Neuroglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/patología , Pioglitazona , Receptores Citoplasmáticos y Nucleares/biosíntesis , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tiazoles/administración & dosificación , Factores de Transcripción/biosíntesis , Tirosina 3-Monooxigenasa/metabolismo
7.
Eur Respir J ; 20(1): 59-65, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12166582

RESUMEN

A case of pulmonary arterial hypertension in a patient with type-Ia glycogen-storage disease, a rare autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase is reported in this study. It has been suggested that the occurrence of pulmonary arterial hypertension in type-Ia glycogen-storage disease could be due to an abnormal production of vasoconstrictive amines such as serotonin. To test this hypothesis, plasma serotonin concentrations were prospectively measured in 13 patients with type-Ia glycogen-storage disease, one patient with severe pulmonary hypertension and type-Ia glycogen-storage disease, 16 patients displaying severe pulmonary arterial hypertension, and 26 normal healthy controls. Elevated plasma serotonin concentrations were found in patients with either severe pulmonary arterial hypertension (38.8+/-7.3 nmol x L(-1)) or type-Ia glycogen-storage disease (36.8+/-11.5 nmol x L(-1)), as compared with controls (8.8+/-0.6 nmol x L(-1), p<0.001). Plasma serotonin was dramatically elevated in the patient with type-Ia glycogen-storage disease and pulmonary arterial hypertension (113.4 nmol x L(-1)). It is concluded that type-Ia glycogen-storage disease may be another condition in which abnormal handling of serotonin is one event in a multistep process leading to severe pulmonary arterial hypertension.


Asunto(s)
Depuradores de Radicales Libres/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/etiología , Serotonina/sangre , Adolescente , Adulto , Niño , Preescolar , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Humanos , Hipertensión Pulmonar/genética , Masculino , Estudios Prospectivos , Índice de Severidad de la Enfermedad
8.
Arthritis Rheum ; 46(6): 1643-50, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12115197

RESUMEN

OBJECTIVE: To quantify the inflammatory cell response in rat air pouch pseudosynovial membrane during monosodium urate monohydrate (MSU) crystal-induced inflammation. METHODS: In the rat air-pouch model, we used a computer-assisted histomorphometric method to quantify cell distributions, based on cell linear densities, in histologic sections of membranes from pouches injected with MSU or saline. The volume, white blood cell (WBC) count, and histamine content of the pouch exudates were determined at several time points. RESULTS: Injection of 10 mg of MSU crystals into the pouch produced an acute exudate. After peaking at 24 hours, the exudate volume and WBC count decreased spontaneously over the next 3 days, simulating the self-limited course of acute gout. Membrane thickness followed a parallel course. Membrane polymorphonuclear cell (PMN) linear densities were closely correlated with exudate WBC counts, suggesting PMN recruitment from the subintimal synovial membrane. Both monocyte/macrophage and mast cell linear densities increased in the subintimal layer 2 hours after crystal injection (P = 0.038 and P = 0.03, respectively, versus controls), whereas PMN linear densities showed 2 peaks, one at 4 hours and the other 24 hours. The exudate histamine content peaked 6 hours after crystal injection, when mast cell linear densities were minimal in the membranes, suggesting mast cell degranulation. CONCLUSION: An increase in monocyte/macrophage and mast cell densities in the membrane preceded the PMN influx in the pouch membrane and exudate, suggesting that mast cells may be involved in the early phase of MSU crystal-induced inflammation, at least in this rat model.


Asunto(s)
Gota/inmunología , Gota/patología , Ácido Úrico/farmacología , Animales , Recuento de Células , Cristalización , Modelos Animales de Enfermedad , Exudados y Transudados/citología , Exudados y Transudados/inmunología , Fibroblastos/citología , Fibroblastos/inmunología , Gota/inducido químicamente , Inflamación/inducido químicamente , Inflamación/patología , Macrófagos/citología , Macrófagos/inmunología , Mastocitos/citología , Mastocitos/inmunología , Monocitos/citología , Monocitos/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Ratas , Ratas Sprague-Dawley , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Ácido Úrico/química
9.
Br J Pharmacol ; 134(7): 1367-74, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11724741

RESUMEN

1. The influence of lipopolysaccharide (LPS)-induced sepsis on the various mast cell phenotypes of rat dura mater were examined both by immunohistochemical and biochemical methods. 2. Three different populations of mast cells were identified in control rats: connective tissue type mast cells (CTMC) which contain rat mast cell protease1 (RMCP1), histamine, serotonin and heparin, mucosal type mast cells (MMC) which contain RMCP2, histamine and serotonin, and intermediate type which contains both RMCP1 and RMCP2 and probably various proportions of amines and heparin. 3. LPS (25 mg kg(-1) i.p.) caused changes in the proportions of the various types of mast cells. The number of MMC and intermediate type mast cells significantly increased and the number of mast cells immunopositive for both heparin and serotonin significantly decreased. Biochemical analysis showed that the histamine concentration of dura increased while its serotonin concentration decreased. 4. While vasoactive intestinal peptide (VIP) (25 ng kg(-1) i.p.) appears to potentiate LPS effects on dura mater mast cells, non-selective inhibition of nitric oxide (NO) synthase by N(g)-nitro-L-arginine methyl ester (L-NAME) (30 mg kg(-1) i.p.) did not influence sepsis-induced mast cell changes. 5. These findings suggest that mast cells of dura mater may play a role in brain protection during sepsis.


Asunto(s)
Duramadre/metabolismo , Mastocitos/metabolismo , Sepsis/fisiopatología , Animales , Recuento de Células , Quimasas , Duramadre/citología , Duramadre/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Heparina/metabolismo , Histamina/metabolismo , Lipopolisacáridos/administración & dosificación , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Microscopía Confocal , NG-Nitroarginina Metil Éster/farmacología , Ratas , Ratas Sprague-Dawley , Sepsis/inducido químicamente , Serina Endopeptidasas/metabolismo , Serotonina/metabolismo , Péptido Intestinal Vasoactivo/farmacología
10.
Am J Respir Crit Care Med ; 164(1): 149-54, 2001 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-11435253

RESUMEN

Pharmacological evidence supports a role of a transient decreased endogenous nitric oxide (NO) synthesis in ovalbumin (OVA)-induced early airway hyperresponsiveness in guinea pigs. However, no data are available regarding the expression and activity of the constitutive NO synthases (cNOS; NOS1 and NOS3, nNOS and eNOS, respectively) in this model. Therefore, we evaluated cNOS activity (conversion of L-[3H]arginine to L-[3H]citrulline in the presence of Ca2+ and calmodulin), nitrate and nitrite (NOx) concentration (modified Griess method), and NOS1 and NOS3 protein expression (Western blot) in lung homogenates and in the tracheal smooth muscle from OVA-immunized and multiple aerosol-challenged guinea pigs (six challenges, once daily). The expression and activity of the inducible NOS isoform (NOS2), the levels of exhaled NO, and the in vivo airway reactivity were also determined. Constitutive NOS activity and NO(x) concentration were significantly lower 6 h after the last OVA challenge as compared with saline exposure, being similar at 24 h. Expression of NOS1 paralleled cNOS activity, which was reduced 6, but not 24 h after OVA challenge. The decrease in NOS1 expression was accompanied by a significant decrease in the amounts of exhaled NO and by a maximal airway hyperresponsiveness to histamine. The levels of NOS3 were not modified at the two time points evaluated, and no NOS2 expression and activity were found at any time point. Similar modifications were observed in the tracheal smooth muscle. We conclude that OVA stimulation in immunized guinea pigs induced a transient reduction in NOS1 protein expression and activity in the respiratory system, which probably participates in airway hyperresponsiveness.


Asunto(s)
Pulmón/inmunología , Músculo Liso/inmunología , Óxido Nítrico Sintasa/metabolismo , Ovalbúmina/inmunología , Tráquea/inmunología , Aerosoles , Animales , Pruebas de Provocación Bronquial , Broncoconstricción/efectos de los fármacos , Cobayas , Histamina/farmacología , Pulmón/enzimología , Masculino , Músculo Liso/metabolismo , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo I , Tráquea/enzimología
11.
Neurosurgery ; 48(3): 626-33; discussion 633-5, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11270554

RESUMEN

OBJECTIVE: We investigated the expression in rabbit basilar arteries of cyclooxygenase (COX)-2, which is the inducible isoform of the enzyme of prostaglandin (PG) production, and the concentrations of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) and representative PGs in the cerebrospinal fluid (CSF) after experimental subarachnoid hemorrhage (SAH). METHODS: Seven sets of basilar arteries were removed from control rabbits and from rabbits killed 1 and 3 days after induced SAH. The arteries were subjected to identical simultaneous immunolabeling for examination with a confocal microscope. One-half of each artery was stained for the constitutive form COX-1 and the other half for COX-2. CSF was sampled in control animals and at 6 hours, 1 day, and 3 days for assays of TNFalpha, PGE2, and 6-keto-PGF1 (metabolite of PGI2). RESULTS: COX-1 immunoreactivity in the endothelial layer was similar in the three groups. Weak endothelial COX-2 immunoreactivity was found in arteries of control animals. COX-2 staining was higher in the group killed at 3 days compared with the control group (P < 0.05). The levels of PGE2 and 6-keto-PGF1alpha in the CSF peaked significantly at 6 hours, then decreased at 3 days to the basal level (PGE2) or significantly lower (6-keto-PGF1). TNFalpha was undetectable in control CSF, significantly higher (P < 0.001) at 6 hours, and undetectable at 3 days. CONCLUSION: After SAH, endothelial COX-1 immunoreactivity does not change, whereas overexpression of COX-2 occurs at 3 days. This induction does not seem linked to TNFalpha production, nor is it responsible for early raised levels of PGE2 and PGI2 in the CSF. We suggest that the role of induced COX-2 may be to modify gene expression and hence alter the properties of the vessel wall after SAH.


Asunto(s)
Arteria Basilar/enzimología , Endotelio Vascular/citología , Endotelio Vascular/enzimología , Isoenzimas/biosíntesis , Peroxidasas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Hemorragia Subaracnoidea/enzimología , Animales , Líquido Cefalorraquídeo/química , Ciclooxigenasa 2 , Regulación de la Expresión Génica , Masculino , Conejos , Factores de Tiempo
12.
Pathol Biol (Paris) ; 48(7): 630-41, 2000 Sep.
Artículo en Francés | MEDLINE | ID: mdl-11072641

RESUMEN

Migraine is one of the few pathologies which gave rise to a tremendous number of physiopathological hypotheses. The variability of its clinical features and of the crisis initiating triggers, together with the numerous functional and/or biological abnormalities reported in migrainous patients, led to multiple 'theories' about migraine. For instance, migraine attacks may be associated with modifications of cerebral blood flow, and/or alterations at the cellular (neuronal and peripheral: platelets, mast cells, etc.) and subcellular (mainly mitochondrial) levels leading to variations of parameters such as serotonin, vasoactive neuropeptides, histamine, nitric oxide, neuroactive amino acids, etc. However, these modifications are mainly related to migraine attacks but not to migrainous patients. These emphasize how important is the distinction between the crisis mechanism(s) and the determinism of migraine illness. Despite the absence of any true animal model of migraine attack, the obtention, through the activation of the trigemino-vascular complex, of an experimental meningeal neurogenic inflammation was a clear breakthrough for the understanding of the migraine attack. Concerning the determinism of migraine, its familial characteristic has been known for a long time, but genetic studies started only recently. Despite some important contributions, the respective roles of genetic and environmental factors, as well as the transmission mode of migraine, remain largely to be determined. Practically, these genetic data, which really concern only a very peculiar form of migraine--the familial hemiplegic one--do not have presently any diagnostic or therapeutic application.


Asunto(s)
Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Receptores de Serotonina/genética , Animales , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Mapeo Cromosómico , Modelos Animales de Enfermedad , Humanos , Trastornos Migrañosos/genética , Modelos Biológicos , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Agonistas de Receptores de Serotonina/uso terapéutico , Vasodilatación
13.
Arterioscler Thromb Vasc Biol ; 20(10): 2233-9, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11031209

RESUMEN

Elevated plasma serotonin is associated with primary pulmonary hypertension (PPH). To test whether this elevation could be related to platelet activation, the 2 pools of blood serotonin (platelets and plasma) and plasma 5-hydroxyindoleacetic acid (5-HIAA) as well as markers of platelet activation (alpha(IIb)beta(3), CD36, P-selectin, and CD63 membrane epitopes) were measured in 16 patients with severe PPH (group 1) before and at days 10 and 40 of treatment with a continuous infusion of epoprostenol (prostacyclin). The same biological parameters were also measured in 19 healthy subjects (group 2) and in 10 patients after cardiovascular surgery with extracorporeal circulation (group 3), a condition known to profoundly activate the platelets. Twelve PPH patients showed hemodynamic and clinical improvement, 3 remained stable, and 1 had the treatment stopped because of clinical aggravation. At day 0, mean plasma serotonin (5-hydroxytryptamine [5-HT]) concentration was much higher in PPH patients than in normal subjects (34.4+/-21.2 versus 9.1+/-6.0 nmol/L, respectively; P:<0.001) and positively correlated with total pulmonary resistance. The mean platelet 5-HT content was not significantly different in PPH compared with normal individuals. Mean plasma 5-HIAA concentrations were much higher in PPH than in normal patients (162+/-57 versus 61+/-7 nmol/L, respectively; P<0.001). These parameters did not significantly change during epoprostenol treatment. There was no correlation between the changes in plasma 5-HT during treatment and clinical or hemodynamic improvement. In PPH patients, the mean platelet volume significantly decreased (ANOVA, P<0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of alpha(IIb)beta(3) and CD36 epitopes. When compared with control platelets, the number of alpha(IIb)beta(3) epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300+/-7140 for PPH patients versus 36 010+/-3930 for control subjects, P=0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590+/-5080 for PPH patients versus 11 900+/-1790 for control subjects), decreased during treatment (ANOVA, P=0.038) and became significantly low at day 40 (8660+/-3520, P<0.001). The number of CD63 epitopes was not elevated, and P-selectin was never detected at any time point on PPH platelets. This glycoprotein profile indicates that the platelets of PPH patients were not highly activated but had an accelerated turnover and returned to normal under epoprostenol treatment without change of the elevated plasma serotonin, characteristic of PPH. In conclusion, neither platelet activation nor a significant alteration of the 5-HT endothelial metabolism explains the high level of plasma 5-HT in PPH patients. The 5-HT plasma concentration is not a predictive marker of the severity of PPH, and its evolution is independent of the clinical and hemodynamic status. Treatment by a potent antiaggregating agent, epoprostenol, does not affect the increase of plasma 5-HT, despite a therapeutic benefit.


Asunto(s)
Antihipertensivos/uso terapéutico , Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Serotonina/sangre , Adulto , Anciano , Análisis de Varianza , Antígenos CD/análisis , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Antígenos CD36/análisis , Femenino , Citometría de Flujo , Hemodinámica , Humanos , Ácido Hidroxiindolacético/análisis , Ácido Hidroxiindolacético/sangre , Hipertensión Pulmonar/sangre , Infusiones Intravenosas , Masculino , Selectina-P/análisis , Activación Plaquetaria , Recuento de Plaquetas , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/análisis , Glicoproteínas de Membrana Plaquetaria/análisis , Serotonina/análisis , Tetraspanina 30
14.
J Biol Chem ; 275(13): 9324-31, 2000 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-10734074

RESUMEN

Taking advantage of three cellular systems, we established that 5-HT(2B) receptors are coupled with NO signaling pathways. In the 1C11 serotonergic cell line and Mastomys natalensis carcinoid cells, which naturally express the 5-HT(2B) receptor, as well as in transfected LMTK(-) fibroblasts, stimulation of the 5-HT(2B) receptor triggers intracellular cGMP production through dual activation of constitutive nitric-oxide synthase (cNOS) and inducible NOS (iNOS). The group I PDZ motif at the C terminus of the 5-HT(2B) receptor is required for recruitment of the cNOS and iNOS transduction pathways. Indeed, the 5-HT(2B) receptor-mediated NO coupling is abolished not only upon introduction of a competitor C-terminal 5-HT(2B) peptide in the three cell types but also in LMTK(-) fibroblasts expressing a receptor C-terminally truncated or harboring a point mutation within the PDZ domain. The occurrence of a direct functional coupling between the receptor and cNOS activity is supported by highly significant correlations between the binding constants of drugs on the receptor and their effects on cNOS activity. The 5-HT(2B)/iNOS coupling mechanisms appear more complex because neutralization of endogenous Galpha(13) by specific antibodies cancels the cellular iNOS response while not interfering with cNOS activities. These findings may shed light on physiological links between the 5-HT(2B) receptor and NO and constitute the first demonstration that PDZ interactions participate in downstream transductional pathways of a G protein-coupled receptor.


Asunto(s)
Isoenzimas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Receptores de Serotonina/fisiología , Secuencia de Aminoácidos , Secuencia de Bases , GMP Cíclico/metabolismo , Cartilla de ADN , Activación Enzimática , Datos de Secuencia Molecular , Óxido Nítrico/biosíntesis , Unión Proteica , Receptor de Serotonina 5-HT2B
15.
Neuroscience ; 96(1): 205-13, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10683424

RESUMEN

Nerve fibres and mast cells are often described in close morphological and functional interactions in various organs such as the dura mater. The respective roles of mast cell activation and sympathetic impairment in cluster headache and migraine attacks have been repeatedly suggested. We have thus investigated the long-term effects of sympathectomy on mast cell morphology and content in the rat dura mater. Fifteen to 60 days after either sham, unilateral or bilateral superior cervical ganglionectomy, dura were removed for either histochemical or biochemical analysis. In the first case, they were fixed and mast cell heparin was stained by fluorescein isothiocyanate-conjugated avidin. Microscopic examination was followed by digital acquisitions using a tomographic process to assess mast cell density in the whole depth of the dura mater. Unilateral ganglionectomy induced a progressive and significant increase in mast cell density 15-60 days post-surgery in contralateral hemi-dura and 30 days post-surgery in ipsilateral hemi-dura. This increase was significant in both dura 60 days after bilateral ganglionectomy. Following perfusion with saline, we also examined the content of histamine and serotonin, pre-formed amines stored in mast cell granules. Biochemical analysis of dura serotonin and histamine content using high-pressure liquid chromatography and radioenzymatic assays, respectively, revealed under all conditions a serotonin tissue concentration lower than that of histamine. After sham ganglionectomy, the dura serotonin content increased from 15 to 60 days post-surgery, whereas the histamine content remained stable over the same period. After unilateral ganglionectomy, the histamine content increased progressively and significantly 30-60 days post-surgery in both hemi-dura, whereas the serotonin content became significantly different from that of sham only 60 days post-surgery in the ipsilateral dura. After bilateral ganglionectomy, the histamine level significantly increased in both hemi-dura 15-60 days post-surgery, whereas the serotonin level had significantly increased at 60 days post-surgery. These results clearly demonstrate, for the first time, a long-term trophic effect of sympathetic nerve degeneration on mast cells in the dura mater. Since mast cell activation has been described previously on the painful side of cluster headache patients during attack periods, we propose that the sympathetic impairment reported in these patients could be prominent, directly or indirectly inducing mast cell hyperplasia and changes in amine contents in the tissue concerned.


Asunto(s)
Duramadre/metabolismo , Histamina/metabolismo , Mastocitos/patología , Serotonina/metabolismo , Ganglio Cervical Superior , Simpatectomía , Animales , Recuento de Células , Hiperplasia , Masculino , Ratas , Ratas Sprague-Dawley , Ganglio Cervical Superior/fisiología , Simpatectomía/métodos
16.
J Infect Dis ; 180(5): 1637-47, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10515827

RESUMEN

The cytokine network and infection severity were characterized during disseminated cryptococcosis in tumor necrosis factor (TNF)- and lymphotoxin (Lt)-alpha-deficient mice. On day 16, the fungus burden was higher and median survival time was reduced, as was polymorphonuclear leukocyte infiltrate in the brains of knockout mice. TNF/Lt-alpha-deficient mice had lower levels of interleukin (IL)-6 in lungs and brains, IL-1beta, and the chemokine KC in brain and spleen and of the chemokine monocyte chemoattractant protein (MCP)-1 in spleen than control animals. In contrast, higher levels of IL-6, IL-10, and MCP-1 in plasma and higher levels of IL-12, interferon (IFN)-gamma, and nitrite/nitrate were found in all compartments of TNF/Lt-alpha-deficient mice. These data confirm that TNF or Lt-alpha is a key cytokine for the anticryptococcal response and demonstrate its major role for the induction of IL-1beta, IL-6, and KC in the brain; however, its presence is not a prerequisite for IL-12, IFN-gamma, and nitrite/nitrate production.


Asunto(s)
Criptococosis/inmunología , Criptococosis/microbiología , Cryptococcus neoformans/crecimiento & desarrollo , Citocinas/biosíntesis , Linfotoxina-alfa/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Encéfalo/inmunología , Encéfalo/patología , Quimiocinas/biosíntesis , Criptococosis/mortalidad , Criptococosis/patología , Femenino , Interferón gamma/biosíntesis , Interleucina-12/biosíntesis , Linfotoxina-alfa/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nitratos/metabolismo , Nitritos/metabolismo , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/genética
17.
Cardiovasc Res ; 43(3): 731-8, 1999 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-10690344

RESUMEN

OBJECTIVE: Growth regulatory properties of nitric oxide (NO) in cultured endothelial cells is controversial. The aim of our study was to investigate the effect of L-arginine, the endogenous NO precursor, and L-NAME, an inhibitor of NO synthase on the reendothelialization process after angioplasty. METHODS: Fifty-five New Zealand White rabbits underwent denudation of the left iliac artery. After injury the rabbits were randomized in three groups: L-arginine 2.25% (L-arginine, n = 19); NG-nitro-L-arginine methyl ester 15 mg/kg/day (L-NAME, n = 19); and placebo (controls, n = 17). Treatment was solubilized in drinking water. Reendothelialization was evaluated at 4 weeks by macroscopic evaluation of Evans blue staining and endothelial-specific immunostaining (CD-31) on cross sections. Intimal hyperplasia was evaluated by morphometric analysis. RESULTS: Despite a significant increase in plasma arginine (P = 0.001) and a reduction in intimal hyperplasia (P = 0.003) with L-arginine, neither agent had a significant effect on reendothelialization at 4 weeks (controls = 36 +/- 4%, L-arginine = 43 +/- 3%, L-NAME = 33 +/- 4%; NS). CONCLUSION: These results suggest that, in spite of previously demonstrated effects on neointimal hyperplasia, the NO pathway does not influence the regrowth of macrovascular endothelial cells in vivo.


Asunto(s)
Arginina/farmacología , Cateterismo/efectos adversos , Endotelio Vascular/patología , Inhibidores Enzimáticos/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Análisis de Varianza , Animales , Arginina/sangre , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hiperplasia , Masculino , Óxido Nítrico/metabolismo , Conejos , Distribución Aleatoria , Factores de Tiempo
18.
Brain Res ; 809(2): 294-6, 1998 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-9853122

RESUMEN

Considerable evidence has linked hydroxyl radicals (.OH) to excitotoxicity. Glutamate infused through a microdialysis probe into rat striatum induced a massive .OH production, which was completely blocked by PBN and attenuated by dizocilpine, 2-amino-5-phosphonopentanoic acid (AP-5), NG-nitro-L-arginine methyl ester (L-NAME) and mepacrine. Thus, we suggest that the neurotoxic effects of glutamate in vivo may derive from an increased formation of .OH resulting from excessive activation of NMDA receptors and downstream enzymes such as NOS and PLA2.


Asunto(s)
Cuerpo Estriado/metabolismo , Ácido Glutámico/farmacología , Radical Hidroxilo/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Óxidos N-Cíclicos , Maleato de Dizocilpina/farmacología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Depuradores de Radicales Libres/farmacología , Hidroxibenzoatos/farmacología , Quelantes del Hierro/farmacología , Microdiálisis , NG-Nitroarginina Metil Éster/farmacología , Neurotoxinas/metabolismo , Óxidos de Nitrógeno/farmacología , Quinacrina/farmacología , Ratas , Ratas Sprague-Dawley
19.
Neurosci Lett ; 242(3): 131-4, 1998 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-9530923

RESUMEN

It was recently reported that neuronal nitric oxide synthase (NOS) generates oxygen-derived free radicals in vitro at low concentrations of L-arginine. Using the microdialysis technique, we monitored both hydroxyl radical (.OH) and nitric oxide (.NO) formation in rat striatum perfused with glutamate (500 mM). .OH and .NO were quantitated in microdialysates by measuring the amounts of the non-enzymatic hydroxylation product of salicylate (2,3-dihydroxybenzoic acid) and the metabolites of .NO (nitrite + nitrate), respectively. .OH levels were dramatically increased during glutamate perfusion, while .NO generation was virtually abolished. .OH production was inhibited by the specific NOS blocker, NG-nitro-L-arginine methyl ester. This effect was not reversed but potentiated by L-arginine. Thus, it is likely that NOS generates oxygen-derived free radicals instead of .NO in brain subjected to highly excitotoxic conditions.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Ácido Glutámico/farmacología , Radical Hidroxilo/metabolismo , Óxido Nítrico Sintasa/metabolismo , Animales , Inhibidores Enzimáticos/metabolismo , Hidroxibenzoatos/metabolismo , Masculino , Microdiálisis , NG-Nitroarginina Metil Éster/farmacología , Neurotoxinas/farmacología , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Ratas , Ratas Sprague-Dawley , Salicilatos/metabolismo , Ácido Salicílico
20.
J Comp Neurol ; 393(2): 169-84, 1998 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-9548695

RESUMEN

Genetic inactivation of monoamine oxidase A (MAOA) in C3H/HeJ mice causes a complete absence of barrels in the somatosensory cortex, and similar alterations are caused by pharmacological inhibition of MAOA in wild type mice. To determine when and how MAOA inhibition affects the development of the barrel field, the MAOA inhibitor clorgyline was administered to mice of the outbred strain OF1 for various time periods between embryonic day 15 (E15) and postnatal day 7 (P7), and the barrel fields were analyzed with cytochrome oxidase and Nissl stains in P10 and adult mice. High-pressure liquid chromatography measures of brain serotonin (5-HT) showed three- to eightfold increases during the periods of clorgyline administration. Perinatal mortality was increased and weight gain was slowed between P3 and P6. Clorgyline treatments from E15 to P7 or from P0 to P7 disrupted the formation of barrels in the anterior snout representation and in parts of the posteromedial barrel subfield (PMBSF). Treatments from P0 to P4 caused similar although less severe barrel field alterations. Clorgyline treatments only during embryonic life or starting on P4 caused no detectable abnormalities. In cases with barrel field alterations, a rostral-to-caudal gradient of changes was noted: Rostral barrels of the PMBSF were most frequently fused and displayed an increased size tangentially. Thus, MAOA inhibition resulting in increased brain levels of 5-HT affects barrel development during the entire first postnatal week, with a sensitive period between P0 and P4. The rostral-to-caudal gradient of changes in the barrel field parallels known developmental gradients in the sensory periphery and in the maturation thalamocortical afferents. The observed barrel fusions could correspond to a default in the initial segregation of thalamic fibers or to a continued, exuberant growth of these fibers that overrides the tangential domain that is normally devoted to individual whiskers.


Asunto(s)
Clorgilina/farmacología , Ratones/fisiología , Inhibidores de la Monoaminooxidasa/farmacología , Corteza Somatosensorial/embriología , Corteza Somatosensorial/fisiología , Animales , Axones/química , Axones/enzimología , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Ácido Hidroxiindolacético/análisis , Embarazo , Serotonina/análisis , Corteza Somatosensorial/citología , Tálamo/química , Tálamo/embriología , Tálamo/fisiología , Vibrisas/inervación
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