Overlesioned hemiparkinsonian non human primate model: correlation between clinical, neurochemical and histochemical changes.
Monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been widely used as animal models of Parkinson's disease (PD). Depending on the method of administration different PD models can be developed. Systemic (iv, sc.) MPTP administration can induce an advanced parkinsonian syndrome. However, systemic administration may require intensive animal care after neurotoxin administration, as well as repeated high doses of MPTP to avoid spontaneous recovery. Unilateral intracarotid artery (ICA) MPTP administration induces a stable hemiparkinsonian syndrome, with the advantage of allowing the animal to groom and feed itself and having a control side in the same animal. However, this unilateral syndrome lacks the bilateral characteristics of advanced PD. Bilateral ICA administration can induce a reliable bilateral syndrome but inherent is the risk of severely impairing the animals and leaving them unable to maintain themselves. This report analyzed the PD model induced by administration of unilateral ICA and subsequent intravenous injections of MPTP in rhesus monkeys. The combined method of MPTP administration induces an advanced stable parkinsonian syndrome, in which the ICA injection of MPTP initiates the parkinsonian syndrome primarily in one hemisphere and the subsequent iv. doses (administered as needed) further deplete the dopamine (DA) system to induce a bilateral lesion in a shorter period of time, with fewer side effects. We studied the relationships between the behavioral, biochemical and histochemical changes related to the combined MPTP treatments to further characterize this model. The monkeys were categorized as presenting mild (stage 2) or moderate (stage 3) parkinsonism based on a parkinsonian rating scale. Postmortem biochemical analysis showed massive DA reduction equally in the caudate nucleus and putamen ipsilateral to ICA MPTP infusion, with varying degrees of DA preservation in the contralateral striatum. Differences between stage 2 and stage 3 were attributed to DA concentrations in the caudate nucleus and putamen of the contralateral hemisphere. Tyrosine hydroxylase immunohistochemistry revealed that the midbrain DA neurons of the group A8, A9, and A10 showed differential vulnerability for MPTP. This finding was similar to that observed in idiopathic PD with significant relationships between the clinical stages and cell losses in the group A9 (substantia nigra pars compacta). Positron emission tomography (PET) using [18F] 6-fluoro-L-m- tyrosine (FMT) showed that uptake (Ki) values correlated well with the biochemical data and are good predictors of DA levels in the contralateral striatal regions. Consistent with the immunohistochemical analysis, PET data also showed significant correlations with all groups of the DA cells. Here we describe an animal model that can play an important role in understanding the symptoms and therapeutic basis of PD since different severities of parkinsonian symptoms can be mimicked.
Oiwa
Yoshitsugu
Y
Center for Functional Imaging, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA.
Eberling
Jamie L
JL
Nagy
Dea
D
Pivirotto
Phillip
P
Emborg
Marina E
ME
Bankiewicz
Krys S
KS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D002339:Carotid Arteries; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D005260:Female; D005462:Fluorine Radioisotopes / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D007269:Injections, Intra-Arterial; D008253:Macaca mulatta; D008297:Male; D009448:Neurochemistry; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology; D014055:Tomography, Emission-Computed / Q000379:methods; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase
D005462:Fluorine Radioisotopes; C080704:6-fluoro-3-tyrosine; D014443:Tyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine