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


Autoři: Jeanette M. Metzger aff001;  Helen N. Matsoff aff001;  Alexandra D. Zinnen aff001;  Rachel A. Fleddermann aff001;  Viktoriya Bondarenko aff001;  Heather A. Simmons aff001;  Andres Mejia aff001;  Colleen F. Moore aff003;  Marina E. Emborg aff001
Působiště autorů: Wisconsin National Primate Research Center, University of Wisconsin–Madison, Madison, WI, United States of America aff001;  Cellular and Molecular Pathology Graduate Program, University of Wisconsin–Madison, Madison, WI, United States of America aff002;  Department of Psychology, University of Wisconsin–Madison, Madison, WI, United States of America aff003;  Department of Medical Physics, University of Wisconsin–Madison, Madison, WI, United States of America aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226999

Souhrn

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.

Klíčová slova:

Cardiac ventricles – Cardiomyocytes – Heart – Inflammation – Nerve fibers – Oxidative stress – Parkinson disease – Positron emission tomography


Zdroje

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