RESUMO
INTRODUCTION: In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat. METHODS: Studies were performed using Male Lewis rats. SC infusion of rotenone (3 mg/kg/day) was performed via an osmotic minipump. IC infusion of rotenone occurred directly into the right medial forebrain bundle at three different dosages. At different times following rotenone infusion, behaviour, histopathology (tyrosine hydroxylase and alpha-synuclein immunocytochemistry), peripheral organ pathology (adrenals, heart, kidney, liver, lung, spleen and stomach) were assessed. In part of the SC and IC rats, BBB transport profiles of the permeability marker sodium fluorescein were determined using microdialysis. RESULTS: SC rotenone failed to produce dopaminergic lesions and led to extensive peripheral organ toxicity. BBB permeability for fluorescein following SC rotenone was changed, however due peripheral toxicity. In contrast, IC rotenone produced a progressive lesion of the nigrostrial dopaminergic pathway over 28 days with no associated peripheral toxicity. IC rotenone also exhibited a large increase in amphetamine induced rotational behaviour. In addition, a few IC rats showed alpha-synuclein immunoreactivity and aggregation. Following IC rotenone, no changes in BBB permeability were detected after 14 days. DISCUSSION: SC rotenone only produced peripheral toxicity. IC rotenone appeared to create a progressive lesion of the rat nigrostrial pathway, and may therefore be a more appropriate model of Parkinson's disease progression, compared with the most commonly used 6-OH-DA rat model.
Assuntos
Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Fluoresceína/farmacocinética , Corantes Fluorescentes/farmacocinética , Neurotoxinas , Doença de Parkinson Secundária/induzido quimicamente , Rotenona , Análise de Variância , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Comportamento Animal , Transporte Biológico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Bombas de Infusão Implantáveis , Masculino , Microdiálise , Atividade Motora , Neurotoxinas/administração & dosagem , Neurotoxinas/toxicidade , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/psicologia , Ratos , Ratos Endogâmicos Lew , Rotenona/administração & dosagem , Rotenona/toxicidadeRESUMO
A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.