The implementation of acute versus chronic animal models for treatment discovery in Parkinson's disease.
Animal models for neuropsychiatric disorders are implemented for the purpose of investigating a single or multiple aspects of a specific disease entity. In Parkinson's disease (PD) several models have been utilised to study the biochemical and behavioural consequences of dopamine (DA) neurone degeneration with the intent of further understanding the aetiology of this disease and improving its treatment. While the bilateral 6-hydroxydopamine (6-OHDA) model has been used to produce a broad spectrum of neurochemical and behavioural deficits characterising DA degeneration in humans, this model is traumatic, labour intensive and is associated with high mortality due to the acute effects of the neurotoxin. Consequently, the unilateral 6-OHDA model was developed and implemented. In this model damage to the ascending DA system is produced on one side of the brain thereby inducing postural rotation. This movement is exaggerated by activating the remaining DA systems with apomorphine or amphetamine thereby making it more quantifiable. In view of the less traumatic effects on homeostasis and relative ease with which this model can be implemented it has been used routinely for the purpose of screening potential anti-Parkinsonian drugs for clinical use. However, like any model, the use of the unilateral rotation model has its limitations. It is proposed that the process of exaggerating DA function using this paradigm limits the discovery of potential anti-PD drugs to those which are effective in counteracting an exaggerated DA response. This factor may account for the high incidence of unwanted side effects including involuntary movement, tardive dyskinaesia (TD) and psychosis which are commonly observed in DA replacement therapy. Secondly, this approach limits potential drug candidates to those acting exclusively on brain DA systems. This too is a problem in the sense that PD is known to be a disease involving numerous systems in the human brain and potential therapies acting via other neurochemical systems are being excluded when this model is used exclusively. The object of the present paper is to report the discovery of a non-DA drug possessing potent anti-Parkinsonian qualities which were revealed using the bilateral 6-OHDA model of PD as a screening tool. When the same drug was retested in the traditional unilateral screening model no effect was observed, while more advanced models confirmed its efficacy. These results illustrate that the implementation of appropriate models for revealing new treatment strategies for PD should be broadly based so that single treatment entities are not exclusively pursued for diseases whose aetiologies are multifaceted. Premature extrapolation of findings from a single, early stage model to its clinical counterpart can be detrimental to advancing new treatment strategies, induce false hope, and increase morbidity in PD patients.
Willis
Gregory L
GL
The Bronowski Institute of Behavioural Neuroscience, Coliban Medical Centre, Kyneton, Victoria, Australia. gwillbro@nex.net.au
Kennedy
Gerard A
GA
D008735:5-Methoxytryptamine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D012399:Rotation; D013995:Time
D000978:Antiparkinson Agents; C053008:ML 23; D008735:5-Methoxytryptamine; D016627:Oxidopamine; D004298:Dopamine