RESUMO
The neuroprotective effects of intravenous rasagiline were investigated in a rat model of stroke. Middle cerebral artery (MCA) occlusion was performed in male rats and the short- (neurological severity score [NSS], infarct size), intermediate- (cognition) and long-term (necrotic area) effects were assessed. A bolus (3 mg/kg) of rasagiline followed by a 3-h infusion (3 mg/kg/h), initiated immediately after MCA occlusion, reduced infarct size by 48.6% and NSS by 32.7% relative to saline treatment. Cognitive function, tested in a water maze 2-3 weeks after occlusion, also significantly improved compared with saline-treated controls. Necrotic brain area was 35-50% smaller with rasagiline than with saline following a single bolus dose. The single bolus rasagiline dose was as effective as a rasagiline bolus followed by rasagiline infusion in short-term outcomes. The neuroprotective effect of rasagiline was fully reproducible when administered at 2 h following occlusion but not after 4 h.
Assuntos
Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Indanos/farmacologia , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Indanos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Degeneração Neural/etiologia , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The study was carried out to demonstrate the effects of bradykinin (BK) on hypertension, hyperinsulinemia, and hypertriglyceridemia in fructose-fed rats, and to determine whether these actions are mediated through nitric-oxide (NO) formation. Eighteen rats, rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet, were studied. BK (0.2 mg/day) was infused intravenously using osmotic pumps attached by a catheter to the jugular vein of 12 rats for 12 days. BK was administered either alone (n = 6) or with concomitant inhibition of NO synthase (n = 6). Six untreated rats served as control. Measurements of systolic blood pressure (indirect method) and levels of insulin and triglyceride in serum were taken every second day. BK infused chronically, induced a marked fall in all parameters as early as the second day of infusion: in blood pressure from 152+/-7 to 126+/-12 mmHg, in insulin from 8.7+/-2.9 to 4.6+/-5.4 pg/mL, and in triglyceride from 308+/-94 to 76+/-19 mg/dL. No such reduction was seen in untreated animals. When BK was administered concurrently with NO synthase inhibitor, blood pressure rose significantly, reaching very high values at the end of treatment. However, the reduction in insulin and triglyceride levels induced by BK was not affected. The capacity of BK to enhance reduction in hyperinsulinemia and hypertriglyceridemia in the fructose-fed rats is not mediated by NO formation. Whether this action of BK is related to a direct effect of this peptide remains to be determined.
Assuntos
Glicemia/análise , Bradicinina/farmacologia , Frutose/administração & dosagem , Insulina/sangue , Lipídeos/sangue , Óxido Nítrico/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Dieta , Inibidores Enzimáticos/farmacologia , Hiperinsulinismo/induzido quimicamente , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertrigliceridemia/induzido quimicamente , Infusões Intravenosas , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Displacement MR images of water in in vitro rat spinal cord were computed from q-space analysis of high b value diffusion-weighted MRI data. It is demonstrated that q-space analysis of heavily diffusion-weighted MRI (qs-DWI) provides MR images in which physical parameters of the tissues such as the mean displacement and the probability for zero displacement of the water molecules are used as contrasts. It is shown that these MR images provide structural information surpassing the spatial resolution of conventional MRI by several orders of magnitude. This imaging methodology was used to follow spinal cord maturation in the rat. It was found that changes in the diffusion characteristics of white matter upon maturation are responsible for the emergence of gray/white matter contrast. The mean displacement of water molecules in the white and gray matter of the mature rat spinal cord was found to be 2-3, and 8-10 microns, respectively. The potential and the limitations of this new imaging methodology for early detection of white matter disorders are discussed.
Assuntos
Imageamento por Ressonância Magnética/métodos , Medula Espinal/fisiologia , Animais , Difusão , Bainha de Mielina/fisiologia , RatosRESUMO
Rasagiline, as the mesylate salt (TVP-1012), is a selective, potent, non-reversible MAO-B inhibitor of the propargylamine type. Current cellular and whole animal studies suggested a potential for neuroprotection by rasagiline. Rasagiline in repeat ip doses of 1-3mg/kg within 16h, or by sustained iv infusion to maintain a 3-h steady-state at corresponding levels, improved the outcome of permanent middle cerebral artery occlusion (MCAO) in the rat. In five independent studies using different protocols, rasagiline improved neurological severity score (NSS) with respect to saline from a high of 8.96 +/- 2.18 (n = 94) at 24h, and 7.64 +/- 2.52 (n +/- 49) at 48h, to a low of 7.13 +/- 2.32 (n = 88) at 24h, and 4.99 +/- 2.31 (n = 68) at 48h. Under the same conditions, there was a decrease in the volume of necrotic brain region determined at 48h by triphenyl tetrazolium chloride (TTC), from a high of 240 +/- 66 (n = 54) to a low of 176 +/- 77 mm(3) (n = 55); and by MRI scan at 48h, from a high of 297 +/- 62 (n = 25), to a low of 209 +/- 63 mm(3) (n = 28). Improvement in NSS was more obvious at 48h post MCAO, at the higher dose, when timing of drug administration was within the interval -30 min to 3 h from MCAO. A 3-h iv infusion of rasagiline caused a maximal reduction in infarct volume of about 49% of control. The (S)enantiomer of rasagiline TVP-1022, not a MAO inhibitor, was less effective, but still significantly different from saline, NSS at 48h 5.6 +/- 2.5 (n = 24) vs. 7.5 +/- 2.5 (n = 24), infarct volume 200 +/- 64 (n = 24) vs. 240 +/- 55 mm(3) (n = 24). Selegiline (n = 19) at corresponding ip doses was not different from saline. Dizocilpine decreased infarct volume from 277 +/- 65 (n = 20) to 203 +/- 52mm(3) (n = 21) but could not improve NSS at 24 or 48h. In this model, rasagiline could have exerted a neuroprotective effect independent of MAO inhibition.