RESUMO
5-fluorouracil (5-FU) is a potent antineoplastic agent used for the treatment of various malignancies. The L-arginine nitric oxide (NO) pathway involved in the pathogenesis of chemotherapy induced kidney damage. This work investigated the beneficial mechanism of L-arginine supplementation in 5-FU induced nephropathy. Eighty male Wistar rats were divided into four equal groups: control group; L-arginine group (378 mg/rat/day for 4 weeks); 5-FU group (189 mg/rat/week for 4 weeks) and L-arginine for 1 week before and 4 weeks concomitant with 5-FU group. At the end of experiment, the kidney functions were assessed and kidneys specimens were processed for paraffin sections and stained with haematoxylin and eosin (H&E), Masson's trichome (MT) and periodic acid-Schiff (PAS) stains. Other sections were processed for immunohistochemical demonstration of caspase-3 and inducible NO synthase (iNOS). Image analyser was used to analyse the results morphometrically and statistically. L-arginine administration to 5-FU treated animals elicited significant reduction in serum urea and creatinine levels, urine volume, urinary protein excretion and kidney/body weight ratio in comparison to fluorouracil treated group. L-arginine improved glomeruloscelerosis, degeneration of convoluted tubules and interstitial fibrosis in 5-FU treated animals. L-arginine attenuated effectively some biochemical and histological changes in 5-FU nephrotoxicity.
RESUMO
Tight regulation of gene expression is achieved by a variety of protein complexes that selectively bind chromatin, modify it and change its transcription competency. Histone acetylases (HATs) and deacetylases (HDACs) play an important role in this process. They can generate transcriptionally active or inactive chromatin through the addition (HATs) or removal (HDACs) of acetyl groups on histones, respectively. Repo-Man is a Protein Phosphatase 1 targeting subunit that accumulates on chromosomes during mitotic exit and mediates the removal of mitotic histone H3 phosphorylations. It was shown recently that Repo-Man also regulates heterochromatin formation in interphase and that its depletion favours the switch between transcriptionally inactive and active chromatin, demonstrating that its role goes well beyond mitosis. Here, we provide the first link between a phosphatase and HDAC complexes. We show that genome-wide Repo-Man binding sites overlap with chromatin regions bound by members of the three HDAC complexes (Sin3a, NuRD and CoREST). We establish that members of the NuRD and Sin3a HDAC complexes interact with Repo-Man by mass spectrometry and that Repo-Man is in close proximity to SAP18 (Sin3a) in interphase as observed by the Proximity Ligation Assay. Altogether, these data suggest a mechanism by which Repo-Man/PP1 complex, via interactions with HDACs, could stabilise gene repression.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Montagem e Desmontagem da Cromatina/fisiologia , Cromatina/metabolismo , Mitose/fisiologia , Proteínas de Transporte/metabolismo , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Proteínas Nucleares/metabolismoRESUMO
Prepulse inhibition (PPI) of the acoustic startle reflex, a measure of sensory gating, is reduced in schizophrenic patients. Dopamine agonists and NMDA receptor antagonists such as phencyclidine (PCP) can disrupt PPI in animals, consistent with both the dopamine and glutamate hypotheses of schizophrenia. In this study, we sought to further characterize the effects of the NMDA antagonist dizocilpine on acoustic startle modulation. Fischer 344 rats were tested after one of three doses of dizocilpine (0.05, 0.2, and 0.5 mg/kg) and assessed for PPI as well as for alterations in baseline startle and prepulse facilitation (PPF). Results showed complete disruption of PPI for each inhibitory trial type after 0.2 and 0.5 mg/kg of dizocilpine. Baseline startle and PPF were enhanced by the low dose but decreased with the moderate and high doses of dizocilpine. Although dizocilpine caused alterations in prepulse modulation of startle similar to dopamine agonists, some effects differ. Unique effects of dizocilpine on sensory gating are discussed in terms of their potential for discriminating subtypes of schizophrenic illness with different underlying pathophysiology.
Assuntos
Nível de Alerta/efeitos dos fármacos , Atenção/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/análogos & derivados , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Animais , Nível de Alerta/fisiologia , Atenção/fisiologia , Relação Dose-Resposta a Droga , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Humanos , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Ratos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/fisiologia , Reflexo de Sobressalto/fisiologiaRESUMO
BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.
Assuntos
Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipercinese/induzido quimicamente , Fatores Etários , Animais , Animais Recém-Nascidos , Ligação Competitiva/fisiologia , Maleato de Dizocilpina/farmacocinética , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Feminino , Hibridização In Situ , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/efeitos dos fármacos , Distribuição Aleatória , Ratos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.
Assuntos
Animais Recém-Nascidos/fisiologia , Comportamento Animal/efeitos dos fármacos , Aminoácidos Excitatórios/toxicidade , Hipocampo/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Dopaminérgicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hibridização In Situ , Atividade Motora/efeitos dos fármacos , Gravidez , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Comportamento Estereotipado/efeitos dos fármacosRESUMO
In unanaesthetized decerebrate spinal cats, bremazocine (0.012-0.2 mg/kg, i.v.) selectively inhibited the late C-fibre reflex discharge, recorded in sectioned lumbo-sacral ventral root filaments, after supramaximal electrical stimulation of the ipsilateral sural or common peroneal nerve. This action was naloxone-reversible. The results suggest that activation of kappa opioid receptors in the spinal cord inhibits the integration of nociceptive, but not locomotor, flexion reflexes.
Assuntos
Analgésicos/farmacologia , Benzomorfanos/farmacologia , Morfinanos/farmacologia , Receptores Opioides/efeitos dos fármacos , Nervos Espinhais/efeitos dos fármacos , Animais , Gatos , Estado de Descerebração , Estimulação Elétrica , Receptores Opioides kappaRESUMO
Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. Several groups of rats were subjected to mononeuropathy following the spared nerve injury model, known to produce evident tactile and cold allodynia and heat hyperalgesia. The activity of the ventrolateral orbital areas was selectively blocked by using either chronic or acute injection of lidocaine, electrolytic lesion, or chemical lesion with kainic acid or 6-hydroxydopamine (6-OHDA). The effects of these manipulations were compared with those following lesion of the somatic sensorimotor cortical areas. Local injection of lidocaine resulted in a reversible depression of all neuropathic manifestations while electrolytic or chemical lesions elicited transient attenuation affecting mainly the heat hyperalgesia and to a lesser extent the cold allodynia. The magnitude of the observed effects with the different procedures used can be ranked as follows: 6-OHDAAssuntos
Mononeuropatias/fisiopatologia
, Dor/fisiopatologia
, Córtex Pré-Frontal/fisiologia
, Córtex Somatossensorial/fisiologia
, Adrenérgicos/toxicidade
, Anestésicos Locais/administração & dosagem
, Anestésicos Locais/uso terapêutico
, Animais
, Temperatura Baixa
, Modelos Animais de Doenças
, Eletricidade/efeitos adversos
, Agonistas de Aminoácidos Excitatórios/toxicidade
, Feminino
, Membro Posterior/inervação
, Membro Posterior/fisiologia
, Temperatura Alta
, Hiperalgesia/fisiopatologia
, Ácido Caínico/toxicidade
, Lidocaína/administração & dosagem
, Lidocaína/uso terapêutico
, Mononeuropatias/induzido quimicamente
, Mononeuropatias/tratamento farmacológico
, Bloqueio Nervoso/métodos
, Oxidopamina/toxicidade
, Dor/induzido quimicamente
, Dor/tratamento farmacológico
, Medição da Dor
, Limiar da Dor/efeitos dos fármacos
, Limiar da Dor/fisiologia
, Estimulação Física
, Córtex Pré-Frontal/anatomia & histologia
, Ratos
, Ratos Sprague-Dawley
, Valores de Referência
, Córtex Somatossensorial/cirurgia
RESUMO
The isolated ileal loop often provides a satisfactory solution to the problem of extensive ureteric defects. Our experience in 18 cases of diseased ureters partially or totally replaced by isolated ileal loops is presented. The indications for the operation and important operative and preoperative details are discussed. The operation presents a definite method for renal conservation in many cases in which nephrectomy would otherwise have been unavoidable.
Assuntos
Íleo/cirurgia , Ureter/cirurgia , Derivação Urinária , Adulto , Apendicectomia , Humanos , Muco/metabolismo , Complicações Pós-Operatórias , Doenças Ureterais/cirurgia , Obstrução Ureteral/etiologia , Refluxo Vesicoureteral/etiologiaRESUMO
Neonatal lesions of the ventral hippocampus in rats produce changes in spontaneous and pharmacologically induced dopamine-dependent behaviors that emerge in early adulthood. Neural mechanisms underlying these changes may have implications for understanding the neurobiology of schizophrenia, putatively a neurodevelopmental disorder. In this study, we evaluated the effects of MK-801 (dizocilpine), on automated measures of distance traveled and stereotypies in adult rats with neonatal (postnatal day 7) lesions, and tested the effects of haloperidol, clozapine and an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) antagonist LY293558 on the MK-801-induced behaviors. The lesioned rats showed significantly greater increases in motor activity after 0.05 and O.1 mg/kg of MK-801 than did controls. Both haloperidol (0.1 and 0.4 mg/kg) and clozapine (4 and 10 mg/kg) reduced hyperlocomotion elicited by 0.2 mg/kg MK-801 in the ventral hippocampus (VH)-lesioned and sham rats. Haloperidol was more potent than clozapine in decreasing MK-801-induced stereotypy, especially in the lesioned rats. Moreover, an AMPA antagonist normalized exaggerated MK-801-induced hyperolocomotion in the lesioned rats at doses that had no effect in controls. These results demonstrate that the lesioned rats are more sensitive to MK-801 during adulthood than control rats, and that antidopaminergic drugs as well as AMPA antagonists antagonize the MK-801-induced behaviors. The neonatal lesion rat model may be useful to further our understanding of the interactions between dopamine and glutamate and their role in the pathophysiology of schizophrenia.