title: The exploration of rotenone as a toxin for inducing Parkinson's disease in rats, for application in BBB transport and PK-PD experiments.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Leiden Amsterdam Center for Drug Research, Leiden University, Division of Pharmacology, Leiden, The Netherlands.
authors.forename: Paulien G M
authors.initials: PG
authors.lastname: Ravenstijn
authors.forename: Mario
authors.initials: M
authors.lastname: Merlini
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Hameetman
authors.forename: Tracey K
authors.initials: TK
authors.lastname: Murray
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ward
authors.forename: Hywel
authors.initials: H
authors.lastname: Lewis
authors.forename: Gareth
authors.initials: G
authors.lastname: Ball
authors.forename: Cathy
authors.initials: C
authors.lastname: Mottart
authors.forename: Christine
authors.initials: C
authors.lastname: de Ville de Goyet
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemarchand
authors.forename: Kristel
authors.initials: K
authors.lastname: van Belle
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Elizabeth C M
authors.initials: EC
authors.lastname: de Lange
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001522:Behavior, Animal; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019793:Fluorescein / Q000493:pharmacokinetics*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics*; D015918:Infusion Pumps, Implantable; D008297:Male; D017551:Microdialysis; D009043:Motor Activity; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000378:metabolism / Q000523:psychology; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D000978:Antiparkinson Agents; D005456:Fluorescent Dyes; D009498:Neurotoxins; D012402:Rotenone; D019793:Fluorescein