Abstract
The impact of age-associated disorders is increasing as the life expectancy of the population increments. Cardiovascular diseases and neurodegenerative disorders, such as Parkinson’s disease, have the highest social and economic burden and increasing evidence show interrelations between them. Particularly, dysfunction of the cardiovascular nervous system is part of the dysautonomic symptoms of Parkinson’s disease, although more studies are needed to elucidate the role of cardiac function on it. We analyzed the dopaminergic system in the nigrostriatal pathway of Parkinsonian and dyskinetic monkeys and the expression of some key proteins in the metabolism and synthesis of catecholamines in the heart: total and phosphorylated (phospho) tyrosine hydroxylase (TH), and membrane (MB) and soluble (S) isoforms of catechol-O-methyl transferase (COMT). The dopaminergic system was significantly depleted in all MPTP-intoxicated monkeys. MPTP- and MPTP + L-DOPA-treated animals also showed a decrease in total TH expression in both right (RV) and left ventricle (LV). We found a significant increase of phospho-TH in both groups (MPTP and MPTP + L-DOPA) in the LV, while this increase was only observed in MPTP-treated monkeys in the RV. MB-COMT analysis showed a very significant increase of this isoform in the LV of MPTP- and MPTP + L-DOPA-treated animals, with no significant differences in S-COMT levels. These data suggest that MB-COMT is the main isoform implicated in the cardiac noradrenergic changes observed after MPTP treatment, suggesting an increase in noradrenaline (NA) metabolism. Moreover, the increase of TH activity indicates that cardiac noradrenergic neurons still respond despite MPTP treatment.
Highlights
Abbreviations catechol-O-methyl transferase (COMT) Catechol-O-methyltransferase DA Dopamine dopamine transporter (DAT) Dopamine transporter L-DOPA Levodopa LIDs L-DOPA-induced dyskinesias left ventricular (LV) Left ventricle MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine NA Noradrenaline NMN Normetanephrine PD Parkinson’s disease right ventricular (RV) Right ventricle SNpc Substantia Nigra pars compacta tyrosine hydroxylase (TH) Tyrosine hydroxylase Ventral Tegmental Area (VTA) Ventral tegmental area
We performed TH and DAT immunostaining in two relevant brain areas in PD in order to confirm that MPTP induced the histopathological model of the disease
PD is a progressive neurodegenerative disorder characterized by the increasing degeneration of dopaminergic neurons in the SNpc, which produces severe motor alterations and non-motor symptoms, including autonomic and cardiovascular d ysfunction[1]
Summary
Abbreviations COMT Catechol-O-methyltransferase DA Dopamine DAT Dopamine transporter L-DOPA Levodopa LIDs L-DOPA-induced dyskinesias LV Left ventricle MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine NA Noradrenaline NMN Normetanephrine PD Parkinson’s disease RV Right ventricle SNpc Substantia Nigra pars compacta TH Tyrosine hydroxylase VTA Ventral tegmental area. The selective loss of dopaminergic cell bodies in the Substantia Nigra pars compacta (SNpc) and Scientific Reports | (2021) 11:19871. Their striatal terminals promote a reduction in dopamine levels, producing the motor a lterations[1]. Studies from cardiac sympathetic neuroimaging indicate that some of the mechanisms involved in PD dysautonomia could be the loss of post-ganglionic noradrenergic n erves[1] and the severe myocardial noradrenaline (NA) d epletion[3]. There are other cardiac potential abnormalities such as increased vesicular permeability[12] or the decrease in NA turnover[13]
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