Slowly progressive dopamine cell loss--a model on which to test neuroprotective strategies for Parkinson's disease?
Making animal models of human disease is a very flawed process. Aspects of the disease can be imitated but models do not necessarily give reliable leads for treatment strategies. When Ungerstedt in Sweden first described the 6-hydroxydopamine (6-OHDA) treated rat model of Parkinson's disease /89/ we knew that the symptoms would not map readily to those of the human disease--rats have four legs after all. On the other hand, the neuropathology looked exactly like end-stage Parkinsonian pathology. That remained true even as we explored other types of neuropathology in the rats /24,43-46,80/. Many of today's treatments for Parkinsonism are developed from pharmacological studies on that model of rats with a chemically induced lesion. However, the 6-OHDA model does not address the important issue of a cure for the disease. The triggers and the time-course of dopamine (DA) cell death in rats are known for nearly every disease model - but for the human disease there is no equivalent knowledge. In the human, the neurons have been dying for a considerable time before the symptoms become obvious and they go on dying even with adequate symptomatic relief /94/, but after intracerebral administration of 6-OHDA to an animal the cells die quickly; all cells are destroyed in less than 5 days /42,88,89/. Thus, we were interested in developing an animal model of DA cell death with a slower time-course. After ibotenic acid injections into rat globus pallidus (GP), DA cells are lost from the ipsilateral substantia nigra over the slower time scale of about six weeks. This time scale has allowed us to test some interventions to prevent the cells from dying. Although some attempts have succeeded, cell death is prevented only for three weeks -beyond that treatments fail and DA cells die. At the moment, this model has at least opened a window into causes of neuronal death in a slower time scale /94/ than previous rodent models.
Brain Mechanisms for Behaviour Unit, Okinawa Institute of Science and Technology Promotion Corporation, Initial Research Project, Okinawa, Japan.
Ann K
AK
Wright
Marianela
M
Garcia-Munoz
Gordon W
GW
Arbuthnott
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D013997:Time Factors
D004281:Docosahexaenoic Acids; D004298:Dopamine