Lorena Cuenca Bermejo¹, M. Pilar Almela Rojo², Pablo Gallo Soljancic¹, José Enrique Yuste³, Vicente De Pablos Vicente¹, Víctor Bautista Hernández⁴, Emiliano Fernández¹, M. Luisa Laorden Carrasco², Maria Trinidad Herrero Ezquerro¹

(1) NEUROCIENCIA CLÍNICA Y EXPERIMENTAL, IMIB-Arrixaca, España
(2) FARMACOLOGÍA CELULAR Y MOLECULAR, IMIB-Arrixaca, España
(3) Departamento de Farmacología. Universidad de Murcia, España (Región de Murcia)
(4) Departamento de Cirugía Cardiovascular. Complejo Hospitalario Universitario A Coruña, España (Galicia)

Several studies have shown that dysfunction of the cardiovascular nervous system is part of the dysautonomic symptoms of Parkinson’s disease (PD), as arrythmia or decrease of myocardial noradrenaline. However, the role of cardiac function in PD is still unclear and more studies are needed to elucidate it. In the present work, we studied possible alterations in the catecholaminergic system that can contribute to noradrenergic deficiency in the hearts of PD patients.

Adult male monkeys (Macaca fascicularis, 4-6 kg, 4-5 years old, R.C. Hartelust BV, Netherlands) were divided into three groups: 1) control (n=4); 2) MPTP (n=4); and, 3) MPTP+L-DOPA (n=4). Animals from the control group were not subjected to treatments nor intoxications. Animals from the groups 2 and 3 (MPTP and MPTP+L-DOPA) were chronically intoxicated with MPTP: intravenously, 1 injection (0.3 mg/kg) every 2 weeks for a period of 7 months. Monkeys from the MPTP+L-DOPA group were daily treated with Madopar® (oral, 100 mg/kg) + Benserazide (25 mg/kg) once they reached a stable Parkinsonism, until dyskinesias were developed. All the animals were sacrificed 4 h after the last L-DOPA administration and brains and hearts were removed. We studied the dopaminergic system in the brain areas of Substantia Nigra pars compacta (SNpc) and striatum of MPTP- and MPTP+L-DOPA-treated monkeys, by immunostaining for tyrosine hydroxylase (TH) and dopamine transporter (DAT). We also analyzed the expression of some key proteins in the metabolism 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 number of dopaminergic neurons in the SNpc and the optical density of TH fibers and DAT in the striatum were significantly decreased in all monkeys intoxicated with MPTP. MPTP- and MPTP+L-DOPA-treated animals also showed a decrease in total TH expression in both the right (RV) and the left ventricle (LV). On the contrary, we found a marked increase of phospho-TH at Ser-40 in both groups (MPTP or MPTP+L-DOPA) in the LV, but this increase was only observed in the RV of the monkeys of the MPTP group. The analysis of MB-COMT levels showed a very significant increase of this isoform in the LV of both MPTP- and MPTP+L-DOPA-treated animals. However, S-COMT levels were not affected.

These results indicate that the membrane isoform of COMT is the main implicated in the cardiac noradrenergic changes in response to MPTP treatment, and suggest an increase in NA metabolism. Additionally, the increase of TH activity (by phosphorylation) in the heart observed in our study indicates that cardiac noradrenergic neurons are able to respond despite MPTP treatment.