21 research outputs found
Experimentální model Huntingtonovy chorey ::reakce subependymové vrstvy postranních mozkových komor na neurodegenerativní proces ve striatu a na fetální neurální transplantát
Transgenic Rat Model of Huntington’s Disease: A Histopathological Study and Correlations with Neurodegenerative Process in the Brain of HD Patients
Rats transgenic for Huntington’s disease (tgHD51 CAG rats), surviving up to two years, represent an animal model of HD similar to the late-onset form of human disease. This enables us to follow histopathological changes in course of neurodegenerative process (NDP) within the striatum and compare them with postmortem samples of human HD brains. A basic difference between HD pathology in human and tgHD51 rats is in the rate of NDP progression that originates primarily from slow neuronal degeneration consequently resulting in lesser extent of concomitant reactive gliosis in the brain of tgHD51 rats. Although larger amount of striatal neurons displays only gradual decrease in their size, their number is significantly reduced in the oldest tgHD51 rats. Our quantitative analysis proved that the end of the first year represents the turn in the development of morphological changes related to the progression of NDP in tgHD51 rats. Our data also support the view that all types of CNS glial cells play an important, irreplaceable role in NDP. To the best of our knowledge, our findings are the first to document that tgHD51 CAG rats can be used as a valid animal model for detailed histopathological studies related to HD in human
Proliferation and Differentiation of Adult Endogenous Neural Stem Cells in Response to Neurodegenerative Process within the Striatum
Effect of Sodium 2,3-Dimercaptopropane-1-Sulphonate (DMPS) on Chronic Daunorubicin Toxicity in Rabbits: Comparison with Dexrazoxane
A possible protective action of DMPS (a dithiol chelating agent) against chronic daunorubicin toxicity in rabbits in comparison with dexrazoxane was investigated. The rabbits were divided into five groups: control (saline, 1 ml/kg i.v.), daunorubicin (3 mg/kg i.v.), DMPS (50 mg/kg i.v.); the remaining two groups were pre-treated either with dexrazoxane (60 mg/kg i.p.) or DMPS (50 mg/kg i.v.) 30 min before administration of daunorubicin (3 mg/kg i.v.). Drugs were given once a week for 10 weeks. Routine biochemical parameters were determined in weeks 1, 5 and 11. In the 11th week, invasive haemodynamic parameters were measured, then the rabbits underwent autopsy, cardiac tissue was examined by light microscopy and scored semiquantitatively. The contents of calcium, potassium, magnesium, iron and selenium were measured in the left heart ventricle. DMPS administered alone was well tolerated and did not cause any major signs of toxicity. It decreased the cardiac content of calcium, but did not affect the iron concentration. In contrast to dexrazoxane, DMPS pre-treatment did not prevent the decline in body weight in weeks 8–11 caused by daunorubicin, actually worsened mortality (26.7% vs 40.0%), did not ameliorate daunorubicin-induced nephrotic syndrome, and did not prevent the occurrence of the severe myocardial lesions. Unlike dexrazoxane, a lack of protective effect of DMPS against chronic daunorubicin toxicity in rabbits was demonstrated. The underlying cause may consist in the fact that DMPS does not efficiently chelate tissue iron and thus may not prevent the formation of oxygen free radicals
A Pilot Study of Matrix Metalloproteinases on the Model of Daunorubicin-induced Cardiomyopathy in Rabbits
Matrix metalloproteinases (MMPs), activated by oxidative stress, play a key role during cardiac remodeling. In the present study we aimed to assess the role of MMPs in experimental cardiomyopathy induced by repeated 10-week administration of daunorubicin (3 mg/kg i.v.) to rabbits. In the daunorubicin group, the plasma cardiac troponin T levels (cTnT – a marker of myocardial necrosis) were significantly increased (p<0.05), commencing with the 8th administration compared with the controls. The amount of collagen (an estimate of fibrosis) was also significantly higher in the daunorubicin group (13.39 ± 0.97 mg/g wet weight) compared to the control group (10.03 ± 0.65 mg/g wet weight). In both groups, the LV MMP-activity was observed only in the gelatine substrate in the 70 kDa region (MMP-2), while no MMPs activities were detectable either in the casein or collagen containing zymograms. At the end of the experiment, the MMP- 2 activity was slightly up-regulated (by 16 %) compared with the controls
A Study of Potential Toxic Effects After Repeated 10-Week Administration of a New Iron Chelator – Salicylaldehyde Isonicotinoyl Hydrazone (SIH) to Rabbits
Salicylaldehyde Isonicotinoyl Hydrazone (SIH) – a Pyridoxal Isonicotinoyl Hydrazone (PIH) analogue – is an effective iron chelator with antioxidant and antimalarial effects, as documented in numerous in vitro studies. However, no toxicological data obtained from in vivo studies have been made available yet. In this study, the potential toxic effects of repeated administration of SIH (50 mg/kg, once weekly, 10 weeks, i.p.), partially dissolved in a 10 % Cremophor solution, on various biochemical, haematological, and cardiovascular parameters and on morphology of selected tissues were investigated in rabbits. The obtained values were compared with data from the control (saline, 1 ml/kg, i.v.) and the Cremophor (10 % Cremophor solution, 2 ml/kg, i.p.) groups. In this study, SIH did not induced marked signs of toxicity: No premature deaths occurred, the body weight increase was comparable with the control and Cremophor groups. Only few and mild changes in some biochemical and haematological parameters could be determined, most of them were noticed also in the control or Cremophor groups. The morphological changes in the kidney were mild and did not manifest in the biochemical examination. The cardiac function was also not affected markedly – the values of left ventricular ejection fraction and systolic time interval did not differ from the values of control group. Only an increased left ventricular contractility (dP/dtmax) was noticed in the SIH group at the end of the experiment as compared to the controls (13354±1191 vs. 9339±647 mmHg/s, resp.). These results seem to be promising from the standpoint of possible clinical use of SIH
Molecular Remodeling of Left and Right Ventricular Myocardium in Chronic Anthracycline Cardiotoxicity and Post-Treatment Follow Up
<div><p>Chronic anthracycline cardiotoxicity is a serious clinical issue with well characterized functional and histopathological hallmarks. However, molecular determinants of the toxic damage and associated myocardial remodeling remain to be established. Furthermore, details on the different propensity of the left and right ventricle (LV and RV, respectively) to the cardiotoxicity development are unknown. Hence, the aim of the investigation was to study molecular changes associated with remodeling of the LV and RV in chronic anthracycline cardiotoxicity and post-treatment follow up. The cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg/week for 10 weeks) and animals were sacrificed either at the end of the treatment or after an additional 10 weeks. Daunorubicin induced severe and irreversible cardiotoxicity associated with LV dysfunction and typical morphological alterations, whereas the myocardium of the RV showed only mild changes. Both ventricles also showed different expression of ANP after daunorubicin treatment. Daunorubicin impaired the expression of several sarcomeric proteins in the LV, which was not the case of the RV. In particular, a significant drop was found in titin and thick filament proteins at both mRNA and protein level and this might be connected with persistent LV down-regulation of GATA-4. In addition, the LV was more affected by treatment-induced perturbations in calcium handling proteins. LV cardiomyocytes showed marked up-regulation of desmin after the treatment and vimentin was mainly induced in LV fibroblasts, whereas only weaker changes were observed in the RV. Remodeling of extracellular matrix was almost exclusively found in the LV with particular induction of collagen I and IV. Hence, the present study describes profound molecular remodeling of myocytes, non-myocyte cells and extracellular matrix in response to chronic anthracycline treatment with marked asymmetry between LV and RV.</p></div