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1.
Br J Clin Pharmacol ; 84(2): 268-279, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29068066

RESUMO

AIMS: Preclinical results suggest therapeutic potential of mild hyperbilirubinemia in T2DM and cardiovascular disease. Translational data are limited, because an appropriate bilirubin formulation for parenteral human use is lacking. Considering its use in both clinical practice and medical research in the past, we explored the feasibility to reintroduce parenteral bilirubin for translational experiments. METHODS: We developed a preparation method in accordance with good manufacturing practice and evaluated the parenteral applicability in healthy volunteers (n = 8). Explorative pharmacokinetic and safety data were compared to the results from a literature study on the former parenteral use of bilirubin. Bilirubin was administered intra-arterially to raise the local plasma concentration in the forearm vascular bed (n = 4) and intravenously to raise the systemic plasma concentration (n = 4). Finally, pharmacokinetic characteristics were studied following a single bolus infusion (n = 3). RESULTS: During parenteral application, no side effects occurred. Adverse events mentioned during the two-week observation period were in general mild and self-limiting. Three more significant adverse events (appendicitis, asymptomatic cardiac arrhythmia and atopic eczema) were judged unrelated by independent physicians. A dose-concentration relationship appeared sufficiently predictable for both intra-arterial and intravenous administration. In line with existing knowledge, bilirubin pharmacokinetics could be described best according to a two-compartment model with a volume of distribution of 9.9 (±2.0) l and a total plasma clearance of 36 (±16) ml per minute. CONCLUSIONS: Supported by previous reports, our data suggest that it is both feasible and safe to perform translational experiments with parenteral albumin bound bilirubin.


Assuntos
Bilirrubina , Hiperbilirrubinemia/sangue , Pesquisa Médica Translacional , Adulto , Bilirrubina/administração & dosagem , Bilirrubina/efeitos adversos , Bilirrubina/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Voluntários Saudáveis , Humanos , Injeções Intra-Arteriais , Injeções Intravenosas , Masculino
2.
Lancet Haematol ; 3(11): e516-e525, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27968820

RESUMO

BACKGROUND: Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative conditioning and haemopoietic cell transplantation would have different mortality outcomes depending on whether or not they had laboratory evidence of Gilbert's syndrome. METHODS: In this retrospective cohort study, we used clinical and laboratory data of patients who had haemopoietic cell transplantation from Jan 1, 1991, to Dec 31, 2011. Patients were included if they had received high-dose conditioning regimens of cyclophosphamide plus total body irradiation (CY/TBI), busulfan plus cyclophosphamide (BU/CY), busulfan plus melphalan plus thioTEPA (BUMELTT), or melphalan before transplant. Patients were excluded if their original consent forms to report transplant outcomes were not signed, if consent was withdrawn, or if they were a prisoner. Patients with Gilbert's syndrome were defined as having laboratory values before the start of conditioning therapy for unconjugated serum bilirubin concentrations of at least 17·1 µmol/L (≥1 mg/dL), normal conjugated serum bilirubin, and no evidence of hepatitis, cholestasis, or haemolysis. We assessed the association of Gilbert's syndrome with overall mortality and non-relapse mortality using adjusted Cox regression models at day 200 after transplantation. FINDINGS: Our study cohort was 3379 patients-1855 (55%) allograft and 1524 (45%) autograft recipients. 211 (6%) patients had Gilbert's syndrome and 3168 (94%) did not have this condition. Most patients were adults (median age 45·8 years [IQR 33·2-55·5]) with haematological malignancies. For overall mortality 664 (20%) patients had died by day 200 after transplant (47 [22%] of 211 who had Gilbert's syndrome vs 617 [19%] of 3168 who did not have Gilbert's syndrome), and for non-relapse mortality 499 (92%) patients had died before relapse was recorded (38 [18%] who had Gilbert's syndrome vs 461 [15%] who did not have Gilbert's syndrome). The effect of Gilbert's syndrome on the risk of overall mortality and non-relapse mortality by transplant day 200 varied between the conditioning regimens and donor groups. In patients conditioned with a myeloablative regimen that contained busulfan (n=1131), those with Gilbert's syndrome (n=60) were at a significantly increased risk of death and non-relapse mortality by day 200 compared with those without Gilbert's syndrome (n=1071; hazard ratio [HR] 2·30, 95% CI 1·47-3·61, p=0·00030; and 2·77, 1·71-4·49, p<0·0001). In patients who received CY/TBI or melphalan conditioning regimens, those with Gilbert's syndrome had similar outcomes to those without Gilbert's syndrome (overall mortality at day 200 HR 0·90, 95% CI 0·60-1·34, p=0·60; non-relapse mortality at day 200: 0·90, 0·56-1·45, p=0·65). Analyses of causes of death and busulfan disposition provided no mechanistic explanation for the differences in mortality. INTERPRETATION: Overall mortality and non-relapse mortality at day 200 after transplant were significantly worse in patients with Gilbert's syndrome who received busulfan-containing myeloablative conditioning regimens, compared with non-Gilbert's syndrome patients. Patients with Gilbert's syndrome should receive busulfan-containing myeloablative conditioning regimens with caution. FUNDING: US National Institutes of Health.


Assuntos
Bilirrubina/efeitos adversos , Bilirrubina/fisiologia , Bussulfano/efeitos adversos , Bussulfano/uso terapêutico , Doença de Gilbert/complicações , Doença de Gilbert/mortalidade , Doença de Gilbert/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto , Bilirrubina/sangue , Bussulfano/farmacocinética , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Hepatopatia Veno-Oclusiva/induzido quimicamente , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Tiotepa/uso terapêutico , Transplante Autólogo/efeitos adversos , Transplante Homólogo/efeitos adversos , Washington , Irradiação Corporal Total
3.
Toxicol Lett ; 240(1): 1-9, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26476400

RESUMO

Hyperbilirubinemia is a common clinical phenomenon observed in human newborns. A high level of bilirubin can result in severe jaundice and bilirubin encephalopathy. However, the cellular mechanisms underlying bilirubin excitotoxicity are unclear. Our previous studies showed the action of gamma-aminobutyric acid (GABA)/glycine switches from excitatory to inhibitory during development in the ventral cochlear nucleus (VCN), one of the most sensitive auditory nuclei to bilirubin toxicity. In the present study, we investigated the roles of GABAA/glycine receptors in the induction of bilirubin hyperexcitation in early developing neurons. Using the patch clamp technique, GABAA/glycine receptor-mediated spontaneous inhibitory synaptic currents (sIPSCs) were recorded from bushy and stellate cells in acute brainstem slices from young mice (postnatal day 2-6). Bilirubin significantly increased the frequency of sIPSCs, and this effect was prevented by pretreatments of slices with either fast or slow Ca(2+) chelators BAPTA-AM and EGTA-AM suggesting that bilirubin can increase the release of GABA/glycine via Ca(2+)-dependent mechanisms. Using cell-attached recording configuration, we found that antagonists of GABAA and glycine receptors strongly attenuated spontaneous spiking firings in P2-6 neurons but produced opposite effect in P15-19 neurons. Furthermore, these antagonists reversed bilirubin-evoked hyperexcitability in P2-6 neurons, indicating that excitatory action of GABA/glycinergic transmission specifically contribute to bilirubin-induced hyperexcitability in the early stage of development. Our results suggest that bilirubin-induced enhancement of presynaptic release GABA/Glycine via Ca(2+)-dependent mechanisms may play a critical role in mediating neuronal hyperexcitation associated with jaundice, implicating potential new strategies for predicting, preventing, and treating bilirubin neurotoxicity.


Assuntos
Bilirrubina/efeitos adversos , Glicina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Núcleo Coclear/efeitos dos fármacos , Núcleo Coclear/metabolismo , Ácido Egtázico/análogos & derivados , Ácido Egtázico/metabolismo , Hiperbilirrubinemia/induzido quimicamente , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores da Glicina/metabolismo
4.
PLoS One ; 9(5): e96171, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24796550

RESUMO

BACKGROUND: Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague-Dawley (SD) rats. METHODS: On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pH = 8.5) was injected into the CM at 10 µg/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test. RESULTS: The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (P<0.001). The early and late mortality of the bilirubin-treated rats were both dramatically higher than those of the controls (P = 0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test. CONCLUSION: By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are available.


Assuntos
Antioxidantes/efeitos adversos , Bilirrubina/efeitos adversos , Cisterna Magna , Modelos Animais de Doenças , Kernicterus , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Bilirrubina/farmacologia , Cisterna Magna/metabolismo , Cisterna Magna/patologia , Kernicterus/induzido quimicamente , Kernicterus/metabolismo , Kernicterus/patologia , Ratos , Ratos Sprague-Dawley
5.
J Biol Chem ; 289(8): 4699-709, 2014 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-24403077

RESUMO

Biological and signaling events that connect developmentally induced hyperbilirubinemia to bilirubin-induced neurological dysfunction (BIND) and CNS toxicity in humans are poorly understood. In mammals, UDP-glucuronosyltransferase 1A1 (UGT1A1) is the sole enzyme responsible for bilirubin glucuronidation, a rate-limiting step necessary for bilirubin metabolism and clearance. Humanized mice that express the entire UGT1 locus (hUGT1) and the UGT1A1 gene, develop neonatal hyperbilirubinemia, with 8-10% of hUGT1 mice succumbing to CNS damage, a phenotype that is presented by uncontrollable seizures. We demonstrate that neuroinflammation and reactive gliosis are prominent features of bilirubin brain toxicity, and a disturbed redox status resulting from activation of NADPH oxidase is an important contributing mechanism found in BIND. Using knock-out mice and primary brain cells, we connect a key pattern recognition receptor, Toll-like receptor 2 (TLR2), to hyperbilirubinemia-induced signaling. We illustrate a requirement for TLR2 signaling in regulating gliosis, proinflammatory mediators, and oxidative stress when neonatal mice encounter severe hyperbilirubinemia. TLR2-mediated gliosis strongly correlates with pronounced neuroinflammation in the CNS with up-regulation of TNFα, IL-1ß, and IL-6, creating a pro-inflammatory CNS environment. Gene expression and immunohistochemistry staining show that hUGT1/Tlr2(-/-) mice fail to activate glial cells, proinflammatory cytokines, and stress response genes. In addition, bilirubin-induced apoptosis was significantly enhanced by blocking TLR2 signaling indicating its anti-apoptotic property. Consequently, a higher neonatal death rate (57.1%) in hUGT1/Tlr2(-/-) mice was observed when compared with hUGT1 mice (8.7%). These results suggest that TLR2 signaling and microglia neuroinflammation are linked to a repair and/or protection mode against BIND.


Assuntos
Bilirrubina/efeitos adversos , Glucuronosiltransferase/metabolismo , Síndromes Neurotóxicas/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Bilirrubina/sangue , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Imunofluorescência , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Hiperbilirrubinemia/sangue , Hiperbilirrubinemia/complicações , Hiperbilirrubinemia/genética , Hiperbilirrubinemia/patologia , Mediadores da Inflamação/metabolismo , Kernicterus/sangue , Kernicterus/complicações , Kernicterus/genética , Kernicterus/patologia , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/genética , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Mutagenesis ; 27(6): 731-5, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22874647

RESUMO

Circulating unconjugated bilirubin (UCB) has been reported to protect against lung and colorectal cancer. The present study aimed to explore, for the first time, whether mildly elevated circulating UCB, as found in Gilbert`s syndrome (GS), is associated with changes of DNA damage. A random 76 individuals, matched for age and gender, were recruited from the general population and allocated into the GS group (UCB ≥ 17.1 µM; n = 38) or control group (UCB <17.1 µM; n = 38). Chromosomal and cytological changes were determined in lymphocytes and buccal cells using the cytokinesis-block micronucleus cytome assay (CBMN) and buccal micronucleus cytome assay (BMcyt). No significant differences were found between GS subjects and the control group in the CBMN and BMcyt determined endpoints. Subsequently, when age dependency of effects were analysed, lower formation of buccal micronucleated cells (by 73.3%) and buccal nuclear buds (by 70.9%) in the GS subgroup ≥ 30 years were found, compared to the GS subgroup <30 years. These findings suggest DNA protection in epithelial tissue of older individuals with GS.


Assuntos
Bilirrubina/sangue , Aberrações Cromossômicas , Ensaio Cometa/métodos , Doença de Gilbert/genética , Testes para Micronúcleos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Bilirrubina/efeitos adversos , Neoplasias Colorretais/patologia , Citocinese , Dano ao DNA , Determinação de Ponto Final , Feminino , Ácido Fólico/sangue , Doença de Gilbert/sangue , Homocisteína/sangue , Humanos , Neoplasias Pulmonares/patologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Vitamina B 12/sangue , Adulto Jovem
7.
Gastroenterol. hepatol. (Ed. impr.) ; 35(6): 411-420, jun. -jul. 2012. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-102929

RESUMO

La osteoporosis es una complicación frecuente en la enfermedad hepática crónica, especialmente en las etapas finales de la enfermedad. El problema es más crítico en los pacientes trasplantados, cuando la pérdida ósea se acelera durante el período inmediatamente después de la cirugía. El principal mecanismo implicado en el desarrollo de osteoporosis en los hepatópatas es el déficit de la formación ósea, por el efecto nocivo de sustancias como la bilirrubina y los ácidos biliares, o bien por el efecto tóxico del alcohol o el hierro sobre los osteoblastos.Para la prevención y el tratamiento de la osteoporosis es recomendable una buena nutrición y la administración de suplementos de calcio y vitamina D. No hay pautas concretas en su tratamiento farmacológico, pero se ha demostrado que los bisfosfonatos son eficaces para aumentar la masa ósea en pacientes con colestasis crónica, con un buen perfil de seguridad (AU)


Osteoporosis is a common complication of chronic liver disease, especially in the final stages. This entity is more critical in liver transplant recipients, when bone loss accelerates during the immediate postoperative period. The main mechanism involved in the development of osteoporosis in liver disease is deficient bone formation due to the harmful effects of substances such as bilirubin and bile acids or the toxic effect of alcohol or iron on osteoblasts.To prevent and treat osteoporosis, good nutrition and calcium and vitamin D supplementation are required. There are no specific recommendations on drug treatment but bisphosphonates are effective in increasing bone mass in patients with chronic cholestasis and have a good safety profile (AU)


Assuntos
Humanos , Osteoporose , Cirrose Hepática/complicações , Bilirrubina/efeitos adversos , Ácidos e Sais Biliares/efeitos adversos , Deficiência de Vitamina D/complicações , Difosfonatos/uso terapêutico
9.
J Matern Fetal Neonatal Med ; 24 Suppl 1: 154-5, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21942616

RESUMO

The incidence of the neurological damage of due to severe neonatal jaundice is increasing mainly due to early discharge from the hospital. However the molecular mechanisms at the basis of the neurological damage are still largely unknown. We here summarize what is known and what is not yet known on how bilirubin may cause cellular damage to selective regions of the brain. This may hopefully help to develop diagnostic and therapeutic strategies for a more effective handling of this invalidating condition.


Assuntos
Bilirrubina/efeitos adversos , Icterícia Neonatal/complicações , Doenças do Sistema Nervoso/etiologia , Bilirrubina/metabolismo , Bilirrubina/fisiologia , Humanos , Recém-Nascido , Icterícia Neonatal/diagnóstico , Icterícia Neonatal/terapia , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/terapia , Traumatismos do Sistema Nervoso/complicações , Traumatismos do Sistema Nervoso/diagnóstico , Traumatismos do Sistema Nervoso/terapia
10.
Neurobiol Dis ; 40(3): 663-75, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20727973

RESUMO

Microglia constitute the brain's immunocompetent cells and are intricately implicated in numerous inflammatory processes included in neonatal brain injury. In addition, clearance of tissue debris by microglia is essential for tissue homeostasis and may have a neuroprotective outcome. Since unconjugated bilirubin (UCB) has been proven to induce astroglial immunological activation and neuronal cell death, we addressed the question of whether microglia acquires a reactive phenotype when challenged by UCB and intended to characterize this response. In the present study we report that microglia primary cultures stimulated by UCB react by the acquisition of a phagocytic phenotype that shifted into an inflammatory response characterized by the secretion of the pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, upregulation of cyclooxygenase (COX)-2 and increased matrix metalloproteinase (MMP)-2 and -9 activities. Further investigation upon upstream signalling pathways revealed that UCB led to the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB at an early time point, suggesting that these pathways might underlie both the phagocytic and the inflammatory phenotypes engaged by microglia. Curiously, the phagocytic and inflammatory phenotypes in UCB-activated microglia seem to alternate along time, indicating that microglia reacts towards UCB insult firstly with a phagocytic response, in an attempt to constrain the lesion extent and comprising a neuroprotective measure. Upon prolonged UCB exposure periods, either a shift on global microglia reaction occurred or there could be two distinct sub-populations of microglial cells, one directed at eliminating the damaged cells by phagocytosis, and another that engaged a more delayed inflammatory response. In conclusion, microglial cells are relevant partners to consider during bilirubin encephalopathy and the modulation of its activation might be a promising therapeutic target.


Assuntos
Bilirrubina/efeitos adversos , Inflamação/metabolismo , Kernicterus/metabolismo , Microglia/metabolismo , Fagocitose/fisiologia , Animais , Bilirrubina/imunologia , Bilirrubina/metabolismo , Western Blotting , Células Cultivadas , Citocinas/metabolismo , Ativação Enzimática/fisiologia , Expressão Gênica , Inflamação/imunologia , Inflamação/patologia , Kernicterus/imunologia , Kernicterus/patologia , Microglia/imunologia , Microglia/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Wistar
11.
Pediatr Res ; 64(3): 270-4, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18458654

RESUMO

Although apnea is common in premature babies, there is a paucity of information concerning the pathophysiologic basis of these episodes and their relationship to other perinatal conditions such as hyperbilirubinemia. Unconjugated hyperbilirubinemia in premature infants, even in moderately high levels, may cause encephalopathy affecting brainstem functions and has been linked to increased incidence of apnea in these infants. Thus, there is a need to clarify mechanisms by which bilirubin may alter respiratory control and induce apnea of prematurity. In this study, bilirubin or placebo was infused i.v. in 9-d-old rat pups (n = 36). Serum hyperbilirubinemia peaked in the first hours after bilirubin infusion. Twenty-four hours after bilirubin infusion, respiration was recorded by plethysmography at rest and under hypercapnic and hypoxic conditions. In treated pups, minute ventilation in room air was significantly reduced, hyperventilatory response to CO2 was blunted, and hypoxic ventilatory depression was increased, compared with placebo-injected rat pups. Brainstem bilirubin deposition and immunoreactivity to bilirubin was detected in the brainstem on histologic analysis. We speculate that high serum bilirubin levels may cause prolonged inhibition of brainstem autonomic function and that this could underlie the exacerbation of apnea noted in premature babies who have experienced jaundice.


Assuntos
Bilirrubina/efeitos adversos , Tronco Encefálico/fisiopatologia , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/fisiopatologia , Fenômenos Fisiológicos Respiratórios , Animais , Animais Recém-Nascidos , Apneia/fisiopatologia , Bilirrubina/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Bulbo/metabolismo , Ventilação Pulmonar/fisiologia , Ratos , Ratos Sprague-Dawley , Albumina Sérica/metabolismo
12.
Neonatology ; 92(4): 219-26, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17556840

RESUMO

BACKGROUND: Extreme hyperbilirubinemia is treated with double volume exchange transfusion, which may take hours to commence. A neuroprotective agent that could be administered immediately might be clinically useful. Minocycline, an anti-inflammatory and anti-apoptotic semisynthetic tetracycline, prevents hyperbilirubinemia-induced cerebellar hypoplasia in Gunn rats. Acute brainstem auditory evoked potential (BAEP) abnormalities occur after giving sulfadimethoxine to 16-day-old jaundiced Gunn rats to displace bilirubin into tissue including brain. OBJECTIVE: To assess whether minocycline is neuroprotective in this model of acute bilirubin encephalopathy. METHODS: We recorded BAEPs at baseline and 6 h after injecting sulfadimethoxine. Minocycline 0.5 mg/kg (n = 4), 5 mg/kg (n = 9), 50 mg/kg (n = 9) or 500 mg/kg (n = 3, all died) was administered 15 min before sulfadimethoxine (0 h). Controls received saline followed by either sulfadimethoxine (n = 13) or saline (n = 7). RESULTS: At 6 h total plasma bilirubin decreased from 10.84 +/- 0.88 mg/dl (mean +/- SD) to 0.70 +/- 0.35 mg/dl (p <10(-9)) in all sulfadimethoxine-injected groups. At 6 h, there was complete protection against decreased amplitudes of BAEP waves II and III and increased I-II and I-III interwave intervals (brainstem conduction times corresponding to I-III and I-V in humans) with 50 mg/kg minocycline, and partial protection with lower doses. CONCLUSIONS: Minocycline 50 mg/kg 15 min prior to an intervention that normally produces acute bilirubin neurotoxicity is neuroprotective in jaundiced Gunn rat pups. Further studies are needed to investigate the temporal course and mechanism of neuroprotection. Minocycline, administered immediately, may be clinically useful in treating extreme neonatal hyperbilirubinemia and preventing kernicterus. We believe our model provides an efficient in vivo model to screen and evaluate new agents that are neuroprotective against bilirubin toxicity and kernicterus.


Assuntos
Antibacterianos/uso terapêutico , Bilirrubina/efeitos adversos , Icterícia/complicações , Kernicterus/prevenção & controle , Minociclina/uso terapêutico , Animais , Animais Recém-Nascidos , Anti-Infecciosos , Bilirrubina/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Icterícia/induzido quimicamente , Icterícia/metabolismo , Kernicterus/fisiopatologia , Masculino , Condução Nervosa/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Gunn , Sulfadimetoxina
13.
Neonatology ; 92(4): 248-57, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17556843

RESUMO

BACKGROUND: Bilirubin encephalopathy or kernicterus is a potentially serious complication of neonatal hyperbilirubinemia. The mechanism of bilirubin-induced neurotoxicity is not known. Many neurological insults are mediated through NMDA receptor activation. OBJECTIVE: We assessed the effect of the NMDA channel antagonist, MK-801 on bilirubin neurotoxicity in vivo and in vitro. METHODS: Bilirubin toxicity in vitro was assessed using trypan blue staining. Sulfadimethoxine injected (i.p.) jaundiced Gunn rat pups exhibit many neurological sequelae observed in human hyperbilirubinemia. Brainstem auditory-evoked potentials (BAEPs), a noninvasive sensitive tool to assess auditory dysfunction due to bilirubin neurotoxicity, were used to assess neuroprotection with MK-801 (i.p.) in vivo. RESULTS: In primary cultures of hippocampal neurons, 20 min exposure to 64:32 microM bilirubin:human serum albumin reduced the cell viability by approximately 50% ten hours later. MK-801 treatment did not protect the cells. MK-801 pretreatment doses ranging from 0.1-4.0 mg/kg did not protect against BAEP abnormalities in Gunn rat pups 6 h after sulfadimethoxine injection. CONCLUSION: Our findings suggest that bilirubin neurotoxicity is not mediated through NMDA receptor activation.


Assuntos
Bilirrubina/efeitos adversos , Maleato de Dizocilpina/farmacologia , Kernicterus/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Anti-Infecciosos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/complicações , Hiperbilirrubinemia/fisiopatologia , Icterícia/induzido quimicamente , Icterícia/complicações , Icterícia/fisiopatologia , Kernicterus/etiologia , Kernicterus/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Gunn , Receptores de N-Metil-D-Aspartato/fisiologia , Sulfadimetoxina
14.
Trends Pharmacol Sci ; 28(5): 200-5, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17416426

RESUMO

Inflammation and immunity result in a wide range of disease processes, including atherosclerosis, vascular thrombosis and sepsis. Heme oxygenase-1 (HO-1) is a key enzyme that is integral to the temporal and spatial regulation of the host response and, together with its products carbon monoxide (CO) and bilirubin, is crucial for maintaining homeostasis and the preservation of function and life. An increasing number of reports demonstrates that HO-1, CO and bilirubin regulate the immune response. As CO and bilirubin enter clinical trials, there are obstacles to be addressed before their full therapeutic potential can be achieved. In this article, we delineate the challenges that lie ahead regarding toxicity, pharmacokinetics and mechanisms of action to be able to take full advantage of the powerful cytoprotective properties of these agents for clinical benefit.


Assuntos
Bilirrubina/farmacologia , Biliverdina/farmacologia , Monóxido de Carbono/farmacologia , Heme Oxigenase-1/metabolismo , Substâncias Protetoras/farmacologia , Aterosclerose/fisiopatologia , Bilirrubina/efeitos adversos , Bilirrubina/farmacocinética , Bilirrubina/uso terapêutico , Biliverdina/uso terapêutico , Monóxido de Carbono/efeitos adversos , Monóxido de Carbono/farmacocinética , Monóxido de Carbono/uso terapêutico , Citoproteção/efeitos dos fármacos , Heme Oxigenase-1/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Substâncias Protetoras/efeitos adversos , Substâncias Protetoras/farmacocinética , Substâncias Protetoras/uso terapêutico , Sepse/fisiopatologia , Trombose/fisiopatologia
15.
Mini Rev Med Chem ; 3(3): 253-6, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12570840

RESUMO

Bilirubin was long considered a useless metabolite of heme catabolism, responsible for the clinical manifestation of jaundice, and potentially toxic in high doses, particularly in neonates. In the past two decades the potent biological properties of bilirubin, particularly as an antioxidant, have been recognised, and this has prompted a number of investigations into this molecule concerning its in vitro and in vivo properties. This review summarises that work, as well as more recent investigations into the potential therapeutic uses of bilirubin.


Assuntos
Bilirrubina/metabolismo , Bilirrubina/uso terapêutico , Animais , Antioxidantes/efeitos adversos , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Bilirrubina/efeitos adversos , Bilirrubina/farmacologia , Humanos , Medicina Tradicional Chinesa , Estrutura Molecular
17.
J Neurosurg ; 96(2): 287-93, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11838803

RESUMO

OBJECT: The mechanisms involved in brain edema formation following intracerebral hemorrhage (ICH) have not been fully elucidated. The authors have found that red blood cell lysis plays an important role in edema development after ICH. In the present study, they sought to determine whether degradation products of hemoglobin cause brain edema. METHODS: Hemoglobin, hemin, bilirubin, or FeCl2 were infused with stereotactic guidance into the right basal ganglia of Sprague-Dawley rats. The animals were killed 24 hours later to determine brain water and ion contents. Western blot analysis and immunohistochemistry were applied for heme oxygenase-1 (HO-1) measurement. The effects of an HO inhibitor, tin-protoporphyrin (SnPP), and the iron chelator deferoxamine, on hemoglobin-induced brain edema were also examined. Intracerebral infusion of hemoglobin, hemin, bilirubin, or FeCl2 caused an increase in brain water content at 24 hours. The HO-1 was upregulated after hemoglobin infusion and HO inhibition by SnPP-attenuated hemoglobin-induced edema. Brain edema induced by hemoglobin was also attenuated by the intraperitoneal injection of 500 mg/kg deferoxamine. CONCLUSIONS: Hemoglobin causes brain edema, at least in part, through its degradation products. Limiting hemoglobin degradation coupled with the use of iron chelators may be a novel therapeutic approach to limit brain edema after ICH.


Assuntos
Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio/fisiologia , Hemoglobinas/efeitos adversos , Hemoglobinas/fisiologia , Animais , Bilirrubina/efeitos adversos , Bilirrubina/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Edema Encefálico/induzido quimicamente , Desferroxamina/farmacologia , Modelos Animais de Doenças , Heme Oxigenase (Desciclizante)/efeitos adversos , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/fisiologia , Heme Oxigenase-1 , Hemina/efeitos adversos , Hemina/fisiologia , Hemoglobinas/efeitos dos fármacos , Masculino , Metaloporfirinas/farmacologia , Protoporfirinas/farmacologia , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Regulação para Cima/fisiologia
18.
Semin Perinatol ; 26(6): 416-24, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12537313

RESUMO

Hyperbilirubinemia and hypoxia are common causes of brain injury in the newborn. To determine the effects of free bilirubin associated with transient hypoxia on developing rat neurons, the cells were exposed to bilirubin (0.25 to 5 micromol/L) and/or to hypoxia for 3 or 6 hours (95% N2-5% CO2). Glutamate receptor antagonists were added to some cultures. Cell death characteristics, energy metabolism, and protein synthesis were analyzed for 96 hours. Bilirubin increased apoptotic cell death. When associated with hypoxia, the neuronal loss was worsened. Bilirubin reduced energy metabolism, whereas a 6-hour exposure to hypoxia increased it for at least 24 hours, with no influence of additional bilirubin. Bilirubin with or without hypoxia induced 2 increases in protein synthesis, at 1 and 72 hours. In this model, bilirubin may promote programmed neuronal death. When bilirubin is associated with hypoxia, the deleterious effects are enhanced. The suppression of bilirubin induced neuronal damage by the NMDA (N-methyl-D-aspartate) receptor antagonist MK801 suggests the involvement of glutamate.


Assuntos
Bilirrubina/farmacologia , Hiperbilirrubinemia/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Animais , Apoptose/fisiologia , Bilirrubina/efeitos adversos , Sobrevivência Celular/fisiologia , Desoxiglucose/metabolismo , Metabolismo Energético/fisiologia , Feminino , Hiperbilirrubinemia/patologia , Leucina/metabolismo , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Prosencéfalo/citologia , Ratos , Ratos Sprague-Dawley
20.
Bull Acad Natl Med ; 185(8): 1417-26; discussion 1427-8, 2001.
Artigo em Francês | MEDLINE | ID: mdl-11974964

RESUMO

UNLABELLED: Clinical observations suggest that bilirubin encephalopathy is often seen in newborn infants presenting not only with hyperbilirubinemia but also with alterations in oxygen transport like in severe anaemia. Since bilirubin and hypoxia have been shown to be detrimental to the central nervous system, the present study was designed to test the additional effects of the two insults on the outcome of cultured neurons from the forebrain of 14 day-old embryos. After 6 days in vitro, neurons were exposed either to bilirubin (0.5 microM) or to bilirubin and hypoxia for 6 hours. Thereafter, cells were reoxygenated for 96 hours in standard conditions. Control cells were kept in normoxia. Cell viability was assessed by the methyltetrazolium method. Cell death (apoptosis or necrosis) was characterized by fluorescent nuclear staining with DAPI. Rates of protein synthesis and energy metabolism in neurons were measured by [3H]leucine and [3H]2-deoxyglucose incorporation, respectively. Data are reported as percentages of change as compared to controls. Each experiment involved 5 to 10 dishes per time point and was repeated 2 to 4 times. RESULTS: Bilirubin reduced cell viability by 24.5% vs controls (p < 0.001) at 96 h while 16% of the neurons exhibited morphological features of apoptosis (p < 0.001). The combination of hypoxia with bilirubin induced a 34% decrease in cell viability (p < 0.001) and the percentage of apoptotic cells was higher than after the exposure to hypoxia or to bilirubin alone. The rate of protein synthesis increased significantly in all experimental conditions as early as 1 h after the onset of the insult and at 48 h post reoxygenation. It increased again at 72 h in the cells exposed to bilirubin or to bilirubin and hypoxia. These sequential changes in synthesis of specific proteins seem to be involved in delayed neuronal death. Bilirubin decreased significantly [3H]2-deoxyglucose incorporation at 24 h while it increased when the neurons were exposed to both bilirubin and hypoxia (+60%, p < 0.001) and decreased thereafter. These data confirm the deleterious effects of bilirubin on neuronal viability, on protein synthesis and metabolic rates. The combination of bilirubin with hypoxia resulted in stronger detrimental effects on neurons than bilirubin alone.


Assuntos
Bilirrubina/efeitos adversos , Hiperbilirrubinemia/complicações , Hipóxia Encefálica/fisiopatologia , Kernicterus/fisiopatologia , Neurônios/patologia , Animais , Antimetabólitos/metabolismo , Técnicas de Cultura de Células , Desoxiglucose/metabolismo , Modelos Animais de Doenças , Humanos , Recém-Nascido , Doenças do Recém-Nascido , Biossíntese de Proteínas
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