Abstract
Parkinson's disease presents nonmotor complications such as autonomic dysfunction that do not respond to traditional anti-parkinsonian therapies. The lack of established preclinical monkey models of Parkinson's disease with cardiac dysfunction hampers development and testing of new treatments to alleviate or prevent this feature. This study aimed to assess the feasibility of developing a model of cardiac dysautonomia in nonhuman primates and preclinical evaluations tools. Five rhesus monkeys received intravenous injections of 6-hydroxydopamine (total dose: 50 mg/kg). The animals were evaluated before and after with a battery of tests, including positron emission tomography with the norepinephrine analog 11C-meta-hydroxyephedrine. Imaging 1 week after neurotoxin treatment revealed nearly complete loss of specific radioligand uptake. Partial progressive recovery of cardiac uptake found between 1 and 10 weeks remained stable between 10 and 14 weeks. In all five animals, examination of the pattern of uptake (using Logan plot analysis to create distribution volume maps) revealed a persistent region-specific significant loss in the inferior wall of the left ventricle at 10 (P<0.001) and 14 weeks (P<0.01) relative to the anterior wall. Blood levels of dopamine, norepinephrine (P<0.05), epinephrine, and 3,4-dihydroxyphenylacetic acid (P<0.01) were notably decreased after 6-hydroxydopamine at all time points. These results demonstrate that systemic injection of 6-hydroxydopamine in nonhuman primates creates a nonuniform but reproducible pattern of cardiac denervation as well as a persistent loss of circulating catecholamines, supporting the use of this method to further develop a monkey model of cardiac dysautonomia.
Highlights
Parkinson’s disease (PD) is a movement disorder associated with degeneration of the nigrostriatal dopaminergic pathway; patients experience nonmotor symptoms, with up to 80% having some form of autonomic dysfunction [1,2,3,4]
Individual animal sensitivity and the tachyphylaxic effect of sympathetic responses to 6-OHDA dosing influenced the time interval between successive doses that ranged from 12 to 100 minutes with the longest period occurring after a cumulative dose of .1.5–3 mg/kg (Table 1; Figure 2B)
Increasing the number of injections and adjusting each dose according to the individual response minimized side effects and reduced time between consecutive doses
Summary
Parkinson’s disease (PD) is a movement disorder associated with degeneration of the nigrostriatal dopaminergic pathway; patients experience nonmotor symptoms, with up to 80% having some form of autonomic dysfunction [1,2,3,4]. Abnormal autonomic control of the heart, is characterized in PD by orthostatic hypotension, an increase in corrected QT intervals (QTc), and reductions in heart rate variability and plasma norepinephrine [6,7,8,9,10]. Cardiac denervation, which may be a component of dysautonomias or found independently in PD patients, [11,12,13,14] is associated with arrhythmias, shortness of breath during exercise, reduced time to peak heart rate, and fatigue [6,15]. New screening tools [7] and treatments are needed
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