Abstract
Objective: Previous evidence was provided that parkinsonian monkeys exhibited significant though incomplete behavioral recovery following a cell therapy consisting of auto-transplantation of adult neural progenitor cells. The aim of the present study was to assess for the first time in this parkinsonian non-human primate model the striatal dopaminergic function, in parallel to further behavioral assessment. In other words, is the behavioral recovery associated to a reversal of dopaminergic function despite the auto-transplanted cells are not dopaminergic. Methods: Striatal dopaminergic function and motor behavior (spontaneous motion activities) were monitored in adult parkinsonian macaques in relation to autologous neural cell ecosystem (ANCE) transplantation. In four MPTP intoxicated macaques, adult progenitor cells derived from cortical biopsies were re-implanted in the same animal after a phase of spontaneous functional recovery. The function of the striatal dopaminergic system was assessed using 18F-DOPA positron tomography imaging and the motor function was quantified. Results: Two parkinsonian animals exhibited severe motor symptoms, which were moderate and transient in two other monkeys. 18F-DOPA striatal uptake decreased by 80% in three animals, consistent with losses of dopaminergic neurons in substantia nigra and reduced striatal density of dopaminergic projections. Six months after autologous transplantation, all animals improved their motor functions. This functional recovery was largely consistent with positron emission tomography results showing some recovery of 18F-DOPA striatal uptake toward baseline value following transplantation. Conclusion: The present data confirm that symptoms are variable across individual parkinsonian monkeys and that autologous neural cell ecosystem transplantation indeed attenuates parkinsonian motor symptoms. Yet the present study provides for the first time evidence in favor of an increase in the striatal dopaminergic activity that correlates with motor recovery in this novel therapeutic approach, although the implanted cells are not dopaminergic.
Highlights
Parkinson’s disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra (SN) pars compacta
Two parkinsonian animals exhibited severe motor symptoms, which were moderate and transient in two other monkeys. 18F-DOPA striatal uptake decreased by 80% in three animals, consistent with losses of dopaminergic neurons in substantia nigra and reduced striatal density of dopaminergic projections
Six months after autologous transplantation, all animals improved their motor functions. This functional recovery was largely consistent with positron emission tomography results showing some recovery of 18F-DOPA striatal uptake toward baseline value following transplantation
Summary
Parkinson’s disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra (SN) pars compacta. In the nonhuman primate (NHP) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of PD, 18F-DOPA PET scan measure of presynaptic dopaminergic integrity is broadly used and gives valuable clues about the nigrostriatal state after MPTP intoxication [8,9]. Both in PD patients and NHP MPTP model, a low number of dopaminergic neurons in the SN is associated with a decrease in 18F-DOPA PET uptake in striatum [10,11]. Widely studied since several decades, the biological mechanisms underlying PD’s etiology remain largely unknown, making the development of efficient therapies a challenge. In spite of positive outcomes of deep brain stimulation and/or levodopa therapies, the progression of the pathology is neither stopped nor reversed [12,13,14,15,16]
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