title: Nonuniform cardiac denervation observed by 11C-meta-hydroxyephedrine PET in 6-OHDA-treated monkeys.
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 (11)C-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.
authors.affiliation: Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Valerie
authors.initials: V
authors.lastname: Joers
authors.forename: Kailie
authors.initials: K
authors.lastname: Seneczko
authors.forename: Nichole C
authors.initials: NC
authors.lastname: Goecks
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Brunner
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Engle
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.forename: R Jerome
authors.initials: RJ
authors.lastname: Nickles
authors.forename: James E
authors.initials: JE
authors.lastname: Holden
authors.forename: Marina E
authors.initials: ME
authors.lastname: Emborg
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000737:chemistry; D004298:Dopamine / Q000097:blood; D004452:Echocardiography; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging*; D008253:Macaca mulatta; D008297:Male; D009474:Neurons / Q000187:drug effects; D009638:Norepinephrine / Q000097:blood; D016627:Oxidopamine / Q000737:chemistry / Q000633:toxicity*; D049268:Positron-Emission Tomography; D054969:Primary Dysautonomias / Q000175:diagnosis; D019275:Radiopharmaceuticals / Q000737:chemistry
chemical_list: D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D015102:3,4-Dihydroxyphenylacetic Acid; C065363:3-hydroxyephedrine; D016627:Oxidopamine; D004809:Ephedrine; D004298:Dopamine; D009638:Norepinephrine