Déficit dopaminérgico y mecanismos compensatorios en la enfermedad de parkinsoncaracterización de un modelo progresivo en el mono tratado con mptp

Resumen

Parkinson's disease (PD) is characterized by a progressive loss of substantia nigra pars compacta (SNc) neurons. The onset of clinical symptoms only occurs after the degeneration has exceeded a certain threshold. In most of the current 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nonhuman primate models, nigrostriatal lesions and the onset of PD symptoms are the result of an acute neuronal degeneration in the SNc caused by high doses injections of MPTP. In order to develop a model that more closely mimics the degeneration pattern of human PD, we eventually established a protocol that produces a progressive parkinsonian state by controlling for dose and intervals of administration of MPTP. Progressive parkinsonism was induced by repeated administration of small doses (0,5 mg/kg) of MPTP (iv) over several months. The animals (n=42) were distributed in five groups using the Kurlan¿s rating scale: control, asymptomatic, recovered, mild parkinsonian, and severe parkinsonian. PET imaging of the striatum was performed in all monkeys. [11C]dihydrotetrabenazine, which binds to monoaminergic vesicles, and [18F]fluoro-l-dopa, a DOPA decarboxylase substrate, were used as ligands. The brains of all monkeys were immunostained to reveal tyrosine hydroxilase (TH), dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) in the striatum, and TH+ cell bodies were counted in the dopaminergic cell groups A8, A9, A10. Immunohistological methods showed progressive loss of all pre-synaptic dopamine markers in the striatum that correlated with the clinical motor status, the loss of dopaminergic cell bodies in substantia nigra and with the striatal binding PETs¿ reductions. Our results support that a progressive but stable PD model can be produced in primates and that serial assessment with 18F-DOPA and 11C-DTBZ PETs provides an effective approach to evaluate progression of dopaminergic depletion in monkeys with MPTP-induced parkinsonism.