RESUMO
PNU-96391A is a weak dopamine (DA) D(2) receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral 6-OH-DA lesions of the median forebrain bundle. Repeated twice daily treatment with L-DOPA and the decarboxylase inhibitor benserazide (15 and 5 mg/kg, IP, respectively), or quinpirole (D(2)/D(3) agonist, 0.1 mg/kg, SC) increased the contralateral rotations measured on day 7 and 14 as compared to day 1. PNU-96391A (10-60 mg/kg, SC, bid.) antagonized the development of behavioral sensitization induced by both agonists. The basal activity of L-DOPA was not affected while a reduction of quinpirole-induced rotations was observed after 30-60 mg/kg, SC of PNU-96391A. Neurochemical analyses confirmed >99 % reductions of striatal DA levels, unilaterally. Concomitant treatment with PNU-96391A and L-DOPA did not affect plasma levels of PNU-96391A indicating that the effects observed are not related to pharmacokinetic interactions. These results suggest that PNU-96391A could be therapeutically useful to prevent the development of behavioral sensitization induced by DA agonists.
Assuntos
Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Doença de Parkinson Secundária/psicologia , Piperidinas/farmacologia , Animais , Antiparkinsonianos/farmacologia , Química Encefálica/efeitos dos fármacos , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Levodopa/metabolismo , Levodopa/farmacologia , Masculino , Feixe Prosencefálico Mediano/fisiologia , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Comportamento Estereotipado/efeitos dos fármacos , Simpatectomia Química , SimpatolíticosRESUMO
We compared the effects of treatment with methylprednisolone or the 21-aminosteroids, U-74389 and U-74006F (Tirilizad mesylate), on hyperoxic lung injury and the associated expression of mRNA for several adhesion molecules in rats. Inhalation of > 95% oxygen for up to 72 hr in Sprague-Dawley rats produced a marked increase in lung weight and an accumulation of fluid in the thorax when compared with air-breathing controls. Hyperoxia also induced a marked neutrophil-rich influx of inflammatory cells into the bronchial lumen as measured by bronchoalveolar lavage. Neutrophil numbers in bronchoalveolar lavage fluid peaked after 60 hr of exposure to s 95% oxygen; this was associated with a marked upregulation of mRNA for the adhesion molecules P-selectin and E-selectin but not VCAM-1. mRNA for ICAM-1 was constitutively expressed at high levels in both air-breathing controls and in the lungs of rats exposed to high concentrations of oxygen. Pretreatment with the 21-aminosteroids reduced hyperoxic lung damage and improved survival times in animals exposed to > 95% oxygen. However, treatment with methylprednisolone significantly decreased survival times. Treatment with U-74389 did not significantly (p > 0.05) inhibit the BAL neutrophilia and did not significantly (p > 0.05) reduce hyperoxia-induced increases in mRNA expression for P-selectin and E-selectin. The inhibition of hyperoxic lung damage coupled with improved survival seen in treated animals suggests that 21-aminosteroids may provide valuable treatments for pulmonary disorders in which oxidant damage has been implicated.
Assuntos
Pneumopatias/induzido quimicamente , Pneumopatias/tratamento farmacológico , Oxidantes , Pregnatrienos/farmacologia , Animais , Antioxidantes/farmacologia , Moléculas de Adesão Celular/genética , Selectina E , Sequestradores de Radicais Livres/farmacologia , Molécula 1 de Adesão Intercelular/genética , Pulmão/metabolismo , Pneumopatias/metabolismo , Masculino , Metilprednisolona/farmacologia , Neutrófilos/fisiologia , Selectina-P , Glicoproteínas da Membrana de Plaquetas/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Molécula 1 de Adesão de Célula VascularRESUMO
Cytokines released from CD4+ T lymphocytes contribute to the pathogenesis of asthma by influencing the differentiation and function of eosinophils, the primary effector cells that cause airway epithelial damage. Using a model of ovalbumin (OA)-induced, eosinophil-rich chronic lung inflammation in sensitized mice, we have defined the role of T lymphocytes further by using three-color flow cytometry to characterize the adhesion and activation antigens that may be associated with the migration of these cells into the lung and airway lumen. OA inhalation in OA-sensitized C57BL/6 mice resulted in an early (6 to 24 h) influx of neutrophils into the bronchial lumen as enumerated by bronchoalveolar lavage (BAL), which was followed by a marked accumulation of lymphocytes and eosinophils between 24 to 72 h. Phenotypic analysis of BAL or lung tissue T cells showed that most Thy-1 CD3+ T cells were CD4+ (CD4: CD8 ratio of 3 to 4:1). The majority (90%) of the T cells in lung or BAL fluid expressed alpha beta T-cell receptors (TCR). Only 3 to 7% of the T cells were gamma delta TCR+ even though almost 25% of the T cells were CD4- CD8-. There were very few natural killer (NK) or B cells in BAL fluid compared with 15% B cells in dissagregated lung tissue. In contrast to T cells in spleen, almost all the lung and BAL T cells were of the memory phenotype, as ascertained by the expression of high levels of CD44 and by the absence of L-selectin and CD45RB on the cell surface. Fifty to ninety percent of lung and BAL T cells from vehicle-sensitized or OA-sensitized and challenged mice expressed the adhesion molecules CD11a (LFA-1), CD54 (ICAM-1), and CD49d (VLA-4). The early T-cell activation marker CD69 was upregulated on 30% of the lung and BAL T cells in OA-sensitized mice after antigen inhalation. When BAL fluid T cells from OA-sensitized and challenged mice were analyzed for their coexpression of adhesion and/or activation molecules, 75% of the cells that expressed one of three adhesion molecules, CD54, CD49d, or CD11a, also expressed at least one of the other two antigens. At least 15% of BAL T cells had all three of these molecules on their cell surfaces. The OA-dependent, temporally regulated emigration of T cells into the bronchial lumen after exposure to aerosolized antigen may be correlated with the accumulation of cells that express the memory phenotype with enhanced expression of adhesion molecules.