Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration

• Published in: PloS one 2020-01, Vol.15 (1), p.e0226999
• Main Authors: Metzger, Jeanette M, Matsoff, Helen N, Zinnen, Alexandra D, Fleddermann, Rachel A, Bondarenko, Viktoriya, Simmons, Heather A, Mejia, Andres, Moore, Colleen F, Emborg, Marina E
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopamine; Activation; Adrenal medulla; Age; Amino acids; Animal tissues; Animals; Aromatic-L-amino-acid decarboxylase; Autopsy; Biology and Life Sciences; Biomarkers; Biomarkers - metabolism; Cardiomyocytes; Catecholamine; Catecholamines; CD36 antigen; CD36 Antigens - metabolism; Disease Models, Animal; Dysautonomia; Fibers; Heart; Heart - innervation; Heart diseases; Histocompatibility antigen HLA; Hydroxylase; Immunoreactivity; Inflammation; Inflammation - pathology; Innervation; Intoxication; Laboratory animals; Macaca mulatta; Male; Medicine and Health Sciences; Methods; Monkeys & apes; Movement disorders; Nerve Degeneration - pathology; Neurodegeneration; Neurodegenerative diseases; Neurotoxins; Norepinephrine; Oxidative Stress; Oxidopamine - pharmacology; Parkinson Disease - pathology; Parkinson's disease; Pioglitazone; Polymethyl methacrylate; Positron emission; Positron emission tomography; PPAR gamma - metabolism; Primary Dysautonomias; Primates; Research and Analysis Methods; Sympathetic Nervous System - pathology; Synuclein; Tomography; Toxins; Tyrosine; Ventricle; Ventricles (cerebral)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0226999

Cardiac dysautonomia is a common nonmotor symptom of Parkinson's disease (PD) associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies for PD cardiac neurodegeneration are not available, and biomarkers of target engagement are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) recapitulates PD cardiac dysautonomia pathology. We recently used positron emission tomography (PET) to visualize and quantify cardiac sympathetic innervation, oxidative stress, and inflammation in adult male rhesus macaques (Macaca mulatta; n = 10) challenged with 6-OHDA (50mg/kg; i.v.). Twenty-four hours post-intoxication, the animals were blindly and randomly assigned to receive daily doses of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5mg/kg p.o.) or placebo (n = 5). Quantification of PET radioligand uptake showed increased oxidative stress and inflammation one week after 6-OHDA which resolved to baseline levels by twelve weeks, at which time pioglitazone-treated animals showed regionally preserved sympathetic innervation. Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and sex matched normal controls (n = 5). In the heart, 6-OHDA-treated animals showed a significant loss of sympathetic nerve fibers density (tyrosine hydroxylase (TH)-positive fibers). The anatomical distribution of markers of sympathetic innervation (TH) and inflammation (HLA-DR) significantly correlated with respective in vivo PET findings across left ventricle levels and regions. No changes were found in alpha-synuclein immunoreactivity. Additionally, CD36 protein expression was increased at the cardiomyocyte intercalated discs following PPARγ-activation compared to placebo and control groups. Systemic 6-OHDA decreased adrenal medulla expression of catecholamine producing enzymes (TH and aromatic L-amino acid decarboxylase) and circulating levels of norepinephrine, which were attenuated by PPARγ-activation. Overall, these results validate in vivo PET findings of cardiac sympathetic innervation, oxidative stress, and inflammation and illustrate cardiomyocyte CD36 upregulation as a marker of PPARγ target engagement.