ABSTRACT
Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.
Subject(s)
Amino Acids/administration & dosage , Disease Models, Animal , Environment , Nanoparticles/administration & dosage , Neuroprotective Agents/administration & dosage , Parkinsonian Disorders/drug therapy , Animals , Drug Delivery Systems/methods , Male , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: Evaluate the utility of Ki-67 label index, p53 expression and flow cytometry-DNA ploidy in the selection of groups to be treated with prophylactic BCG and the prognostic value compared with the classic variables (grade, lymphatic permeation, multiplicity, volume, primary). MATERIAL & METHOD: 121 superficial bladder tumors T1. 10% Cut-off level for Ki-67 and p53. Aneuplody is defined as a tumor with DNA index different of 1 or more than 20% in G2-M phase. 71 (58.7%) received BCG. RESULTS: In uni and multivariate analysis positivity to Ki-67 is correlated with recurrence. Progression is correlated with lymphatic permeation (p .0003), volume (p .016), ploidy (p .022) and positivity to p53 (p .007). In multivariate analysis, volume and positivity to p53 are independent variables. None were of utility to prevent recurrence, but Ki-67 positive or aneuploid treated tumors had less progression (p .025 and p .009 respectively). The p53 negative treated tumors had less progression too. CONCLUSIONS: Only Ki-67 is correlated with tumoral recurrence. P53 and tumor volume are correlated with stage progression. If the results are confirmed with bigger series, the Ki-67 positive and/or aneuploid tumors would obtain benefits of prophylactic treatment with BCG.
Subject(s)
Adjuvants, Immunologic/therapeutic use , BCG Vaccine/therapeutic use , Gene Expression Regulation, Neoplastic/genetics , Ki-67 Antigen/genetics , Ploidies , Tumor Suppressor Protein p53/biosynthesis , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/prevention & control , Aged , Female , Flow Cytometry , Humans , Male , Neoplasm Staging , Prognosis , Retrospective Studies , Tumor Suppressor Protein p53/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
OBJETIVO: Valorar la utilidad del índice Ki-67, la expresión de proteína p53 y la ploidía de ADN para seleccionar grupos que se beneficien de terapia profiláctica con BCG y la capacidad pronóstica comparándola con las variables clásicas (grado, permeación linfática, volumen tumoral, multiplicidad, primario). MATERIAL Y MÉTODO: 121 carcinomas vesicales T1. Nivel de corte para Ki-67 y p53 del 10 por ciento. Se considera aneuploide cuando el tumor tiene un índice de ADN distinto de 1 ó más del 20 por ciento de la población en fase G2-M. 71 (58,7 por ciento) recibieron BCG. RESULTADOS: Ninguna de las variables clásicas tiene valor pronóstico para recidiva, y de las tres técnicas utilizadas sólo el ser Ki-67 positivo (p 0.001), confirmándose en el estudio multivariante. Para progresión tumoral alcanzan significación, la permeación linfática (p 0.0003), el volumen tumoral (p .016), la ploidía (p 0.022) y la positividad para p53 (p 0.007), confirmándose en el estudio multivariante el volumen tumoral y la positividad para p53. Ninguna de las variables fue útil para seleccionar grupos que disminuyeran su recidiva tumoral. Sin embargo los tumores aneuploides y/o Ki-67 positivos que recibieron tra-tamiento profiláctico progresaron menos (p 0.009 y p 0.025 respectivamente). Los p53 negativos tratados también progresaron menos (p 0.040).Combinando las variables, sólo los Ki-67 positivo y aneuploides se benefician de tratamiento (p 0.031). CONCLUSIONES: Ki-67 es la única variable que se correlaciona con recidiva tumoral. La progresión a estadio infiltrante se correlaciona con la positividad para p53 y el volumen tumoral. Si los resultados se confirman en series más amplias, los tumores Ki-67 positivos y/o aneuploides se beneficiarían de tratamiento profiláctico con BCG (AU)
