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Modelling parkinsonian akinesia and dyskinesia in dopamine depleted rodents

Lundblad, Martin LU (2004)
Abstract (Swedish)
Popular Abstract in Swedish

Parkinsons sjukdom är en av de vanligaste neurologiska sjukdomarna i västvärlden. Vad som orsakar sjukdomen är fortfarande okänt men det betyder sannolikt att det är många faktorer som samverkar för att leda fram till sjukdomen. De mest framträdande symptomen i Parkinsons sjukdom är stelhet, oförmåga att initiera rörelser (s.k. akinesi), balanssvårigheter och tremor (darrningar). De motoriska störningarna vid Parkinsons sjukdom härleds till bristen på signalsubstansen dopamin i hjärnan. Det är nämligen känt att Parkinsons sjukdom leder till att celler som producerar dopamin dör. Med tiden försvinner fler och fler dopamin producerande celler och bristen på dopamin leder till de symptom som nämnts... (More)
Popular Abstract in Swedish

Parkinsons sjukdom är en av de vanligaste neurologiska sjukdomarna i västvärlden. Vad som orsakar sjukdomen är fortfarande okänt men det betyder sannolikt att det är många faktorer som samverkar för att leda fram till sjukdomen. De mest framträdande symptomen i Parkinsons sjukdom är stelhet, oförmåga att initiera rörelser (s.k. akinesi), balanssvårigheter och tremor (darrningar). De motoriska störningarna vid Parkinsons sjukdom härleds till bristen på signalsubstansen dopamin i hjärnan. Det är nämligen känt att Parkinsons sjukdom leder till att celler som producerar dopamin dör. Med tiden försvinner fler och fler dopamin producerande celler och bristen på dopamin leder till de symptom som nämnts ovan. Det finns idag inte något bot för sjukdomen men symptomen kan effektivt lindras med mediciner. Den absolut mest effektiva medicinen heter L-DOPA. L-DOPA är ett förstadium till signalsubstansen dopamin, som det alltså är brist på vid Parkinsons sjukdom. L-DOPA hjälper effektivt mot bland annat akinesi och många patienter återfår till en början till stor del sin vanliga rörlighet. Tyvärr är L-DOPA-behandling inte fri från biverkningar. Efter några års behandling med L-DOPA utvecklar upp till 80% av patienterna så kallade dyskinesier eller onormala ofrivilliga rörelser. Dyskinesier är ett stort handikapp och i allvarliga fall är dessa biverkningar lika handikappande som Parkinsons sjukdom i sig. Vad som orsakar dessa ofrivilliga rörelser är relativt okänt. För att effektivt kunna forska kring uppkomsten av dessa biverkningar krävs tillförlitliga djurmodeller av tillståndet. Länge har all forskning på detta område utförts på apor men under senare år har modeller utvecklats, framförallt av vår grupp, där dessa fenomen kan studeras på råttor och möss. Råttor och möss som behandlats med ett gift som dödar de dopamin-producerande celler utvecklar nämligen symptom som liknar de vid Parkinsons sjukdom. Behandlas dessa djur sedan med L-DOPA uppkommer onormala, ofrivilliga rörelser precis som hos patienter. I mitt avhandlingsarbete har jag studerat modeller av L-DOPA inducerade dyskinesier i gnagare samt utvecklat och utvärderat olika typer av test för att på ett effektivt sätt kunna studera “parkinsonistiska” och “dyskinetiska” fenomen i dessa modeller. Jag har även utvecklat en helt ny modell av Parkinsons sjukdom och dyskinesier i möss. Med en modell i möss öppnas vägen för studier av transgena möss, alltså möss där vissa gener som misstänks vara relevanta för symptom-utvecklingen har modifierats. Att kunna använda dessa möss i vår forskning är ett stort framsteg eftersom man på detta vis mycket grundligt kan undersöka intressanta signalvägar i hjärnceller och samtidigt studera hur förändringar av signalvägarna påverkar djurens beteende med avseende på parkinsonistiska symptom. Mitt arbete visar att på stora likheter mellan de fenomen som ses i parkinsonistiska gnagare och de som ses i patienter med Parkinsons sjukdom. Utvecklandet av dessa modeller kommer att betyda mycket för forskning kring både nya metoder för behandling och biverkningarnas orsaker i framtiden. (Less)
Abstract
Animal models of Parkinson’s disease and L-DOPA-induced dyskinesia are essential to explore pathophysiological hypotheses and to test new treatment options. There are many different animal models of Parkinson's disease, which differ greatly with respect to species, mechanisms of nigral cell death, and extent of dopamine-dependent motor deficits. My work has been performed in rats and mice with unilateral 6-hydroxydopamine (6-OHDA) lesions, as this model is cost-effective and is well characterized. The animals show the main motor symptoms of Parkinsons disease such as akinesia, bradykinesia and postural instability. Previously work have shown that chronic L-DOPA treatment induces abnormal involuntary movements (AIMs) in unilaterally 6-OHDA... (More)
Animal models of Parkinson’s disease and L-DOPA-induced dyskinesia are essential to explore pathophysiological hypotheses and to test new treatment options. There are many different animal models of Parkinson's disease, which differ greatly with respect to species, mechanisms of nigral cell death, and extent of dopamine-dependent motor deficits. My work has been performed in rats and mice with unilateral 6-hydroxydopamine (6-OHDA) lesions, as this model is cost-effective and is well characterized. The animals show the main motor symptoms of Parkinsons disease such as akinesia, bradykinesia and postural instability. Previously work have shown that chronic L-DOPA treatment induces abnormal involuntary movements (AIMs) in unilaterally 6-OHDA lesioned rats. It has been one of the main aims with this thesis to investigate wheter these movements are the rat equivalent of L-DOPA induced dyskinesia. Additionally I have developed and validated a new model of L-DOPA induced (AIMs) in mice. In yet another study the levels of L-DOPA was measured in the brain and blod in dyskinetic and non-dyskinetic animals after an i.p. injection of L-DOPA. In the validation studies, the effects of antiparkinsonian agents that are associated with low incidence of dyskinesia in patients were evaluated using sensitive behavioural test of motor function and the animals AIMs were monitored using the rodent AIMs rating scale. In a later stage, agents with documented antidyskinetic properties in patients, were tested for their ability to reduce the severity of rodent AIMs. The results from both the rat and the mouse studies shows that dopamine-depleted rodents develop AIMs with chronic L-DOPA treatment. The severity of the rodent AIM scores increased with continuing L-DOPA treatment, which conforms to the situation described in treated PD patients. The fact that rodent AIMs were induced by L-DOPA but not by dopamine agonists (such as ropinirole and bromocriptine) implies that the mechanisms underlying rodent abnormal involuntary movements are similar to those underlying L-DOPA induced dyskinesia in PD patients and non-human primate models. This is further corroborated by the fact that several non-dopaminergic drugs known to possess antidyskinetic properties in PD patients also reduced rodent AIM scores. The measurements of central and peripheral L-DOPA levels showed that even though the L-DOPA concetration in the blood did not differ between dyskinetic and non-dyskinetic animals, the extracellular striatal levels of L-DOPA were significantly higher in the dyskinetic animals. These results indicate that a different bioavailability of L-DOPA in the striatal extracellular fluid may provide a clue as to why certain rats develop dyskinesia during chronic L-DOPA treatment and other rats appear resistant. It can be concluded from the results in this thesis that the rodent models are well suited for being used in screening studies for novel antiakinetic and antidyskinetic treatments that will benefit patients with these symptoms as new and more efficient drugs and treatments. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Bezard, Erwan, Bordeaux, France
organization
publishing date
type
Thesis
publication status
published
subject
keywords
neuropsychology, neurophysiology, Neurologi, neuropsykologi, neurofysiologi, Neurology, mouse, rat, 6-OHDA, dyskinesia, Parkinson's disease, L-DOPA
pages
156 pages
publisher
Martin Lundblad, Basal Ganglia, Lund University
defense location
Segerfalksalen, Wallenberg Neurocentrum
defense date
2004-10-02 10:15
ISBN
91-628-6221-9
language
English
LU publication?
yes
id
ee5705fd-a163-46d2-8531-478a8fab17ec (old id 467286)
date added to LUP
2007-10-13 14:19:40
date last changed
2016-09-19 08:45:11
@misc{ee5705fd-a163-46d2-8531-478a8fab17ec,
  abstract     = {Animal models of Parkinson’s disease and L-DOPA-induced dyskinesia are essential to explore pathophysiological hypotheses and to test new treatment options. There are many different animal models of Parkinson's disease, which differ greatly with respect to species, mechanisms of nigral cell death, and extent of dopamine-dependent motor deficits. My work has been performed in rats and mice with unilateral 6-hydroxydopamine (6-OHDA) lesions, as this model is cost-effective and is well characterized. The animals show the main motor symptoms of Parkinsons disease such as akinesia, bradykinesia and postural instability. Previously work have shown that chronic L-DOPA treatment induces abnormal involuntary movements (AIMs) in unilaterally 6-OHDA lesioned rats. It has been one of the main aims with this thesis to investigate wheter these movements are the rat equivalent of L-DOPA induced dyskinesia. Additionally I have developed and validated a new model of L-DOPA induced (AIMs) in mice. In yet another study the levels of L-DOPA was measured in the brain and blod in dyskinetic and non-dyskinetic animals after an i.p. injection of L-DOPA. In the validation studies, the effects of antiparkinsonian agents that are associated with low incidence of dyskinesia in patients were evaluated using sensitive behavioural test of motor function and the animals AIMs were monitored using the rodent AIMs rating scale. In a later stage, agents with documented antidyskinetic properties in patients, were tested for their ability to reduce the severity of rodent AIMs. The results from both the rat and the mouse studies shows that dopamine-depleted rodents develop AIMs with chronic L-DOPA treatment. The severity of the rodent AIM scores increased with continuing L-DOPA treatment, which conforms to the situation described in treated PD patients. The fact that rodent AIMs were induced by L-DOPA but not by dopamine agonists (such as ropinirole and bromocriptine) implies that the mechanisms underlying rodent abnormal involuntary movements are similar to those underlying L-DOPA induced dyskinesia in PD patients and non-human primate models. This is further corroborated by the fact that several non-dopaminergic drugs known to possess antidyskinetic properties in PD patients also reduced rodent AIM scores. The measurements of central and peripheral L-DOPA levels showed that even though the L-DOPA concetration in the blood did not differ between dyskinetic and non-dyskinetic animals, the extracellular striatal levels of L-DOPA were significantly higher in the dyskinetic animals. These results indicate that a different bioavailability of L-DOPA in the striatal extracellular fluid may provide a clue as to why certain rats develop dyskinesia during chronic L-DOPA treatment and other rats appear resistant. It can be concluded from the results in this thesis that the rodent models are well suited for being used in screening studies for novel antiakinetic and antidyskinetic treatments that will benefit patients with these symptoms as new and more efficient drugs and treatments.},
  author       = {Lundblad, Martin},
  isbn         = {91-628-6221-9},
  keyword      = {neuropsychology,neurophysiology,Neurologi,neuropsykologi,neurofysiologi,Neurology,mouse,rat,6-OHDA,dyskinesia,Parkinson's disease,L-DOPA},
  language     = {eng},
  pages        = {156},
  publisher    = {ARRAY(0xa2dbe38)},
  title        = {Modelling parkinsonian akinesia and dyskinesia in dopamine depleted rodents},
  year         = {2004},
}