No abstract

The non-human primate MPTP model of Parkinson’s disease is an essential tool for translational studies. However, the currently used methodologies to produce parkinsonian monkeys do not follow unified criteria, and the applied models may often fall short of reproducing the characteristics of patients in clinical trials. Pooling of data from the parkinsonian monkeys produced in our Centers provided the opportunity to evaluate thoroughly the behavioral outcomes that may be considered for appropriate modeling in preclinical studies. We reviewed records from 108 macaques including rhesus and cynomolgus species used to model moderate to advanced parkinsonism with systemic MPTP treatment. The attained motor disability and the development of levodopa-induced dyskinesias, as primary outcomes, and the occurrence of clinical complications and instability of symptoms were all analyzed for correlations with the parameters of MPTP administration and for estimation of sample sizes. Results showed that frequently the MPTP-treated macaque can recapitulate the phenotype of patients entering clinical trials, but to produce this model consistently it is important to adapt the MPTP exposure tightly according to individual animal responses. For studies of reduced animal numbers it is also important to produce stable models, and stability of parkinsonism in macaques critically depends on reaching “marked” motor disability. The analyzed data also led to put forward recommendations for successfully producing the primate MPTP model of Parkinson’s disease for translational studies.

Objective: Effective medical management of L-dopa induced dyskinesia (LID) remains an unmet need for patients with Parkinson’s disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed antagonist/agonist analgesic nalbuphine in reducing LID and its molecular markers in the non-human primate model. Methods: MPTP-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline s.c. as: 1) monotherapy, 2) acute co-administration with L-dopa, and 3) chronic co-administration for a month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma L-dopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. Results: Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-parkinson effect of L-dopa or changing plasma L-dopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine co-administered with L-dopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine co-therapy blocks several molecular correlates of LID including over-expression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5 (Cdk5), and increased phosphorylation of DARPP-32 at Threonine34. Interpretation: Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.

Long-term dopamine (DA) replacement therapy in Parkinson’s disease (PD) leads to the development of abnormal involuntary movements known asl-Dopa–induced dyskinesia (LID). The transcription factor ΔFosB that is highly up-regulated in the striatum following chronicl-Dopa exposure may participate in the mechanisms of altered neuronal responses to DA generating LID. To identify intrinsic effects of elevated ΔFosB onl-Dopa responses, we induced transgenic ΔFosB overexpression in the striatum of parkinsonian nonhuman primates kept naïve ofl-Dopa treatment. Elevated ΔFosB levels led to consistent appearance of LID since the initial acutel-Dopa tests. In line with this motor response, striatal projection neurons (SPNs) responded to DA with changes in firing frequency that reversed at the peak of the motor response, and these unstable SPN activity changes in response to DA are typically associated with the emergence of LID. Transgenic ΔFosB overexpression also induced up-regulation of other molecular markers of LID. These results support an autonomous role of striatal ΔFosB in the adaptive mechanisms altering motor responses to chronic DA replacement in PD.

Background To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson’s disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative actions on dopaminergic neurons are needed. New Method We developed a methodology for evaluating the effects of a synthetic neuroactive peptide, DNSP-11, on the nigrostriatal system using repeated intranasal delivery in both normal and a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. Results Normal rats repeatedly administered varying doses of DNSP-11 intranasally for 3 weeks exhibited a significant increase in dopamine (DA) turnover in both the striatum and substantia nigra (SN) at 300 μg, suggestive of a stimulative effect of the dopaminergic system. Additionally, a protective effect was observed following repeated intranasal administration in 6-OHDA lesioned rats, as suggested by: a significant decrease in d-amphetamine-induced rotation at 2 weeks; a decrease in DA turnover in the lesioned striatum; and an increased sparing of tyrosine hydroxylase (TH) positive neurons in a specific sub-region of the lesioned substantia nigra pars compacta. Finally, tracer studies showed 125I-DNSP-11 distributed diffusely throughout the brain, including the striatum and SN, as quickly as 30 minutes after a single intranasal dose. Comparison with Existing Methods The results of bilateral intranasal administration of DNSP-11 are compared to our unilateral single infusion studies to the brain in rats. Conclusions These studies support that DNSP-11 can be delivered intranasally and maintain its neuroactive properties in both normal rats and in a unilateral 6-OHDA rat model of PD.