Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson’s disease

Abstract

Patients with Parkinson's disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA-treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment.

Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

“…All data described above are related to physiological conditions; however, in the present study, we verified that in a model of PD, there was a reduction in the number of phox2b-expressing neurons in the NTS region that could be correlated with the loss of autonomic and respiratory function (Falquetto et al, 2017;Oliveira et al, 2017;Tuppy et al, 2015). For example, we showed before that disruption of phox2b-expressing neurons in the NTS impacts the proper function of cardiovascular reflexes (Falquetto et al, 2017). A significant number of PD patients have orthostatic hypotension, suggesting a cardiovascular dysautonomia (Goldstein, 2003).…”

“…In addition, pharmacological blockade of the NTS attenuates the ventilatory and cardiovascular responses to chemoreceptor activation (Berger & Cooney, 1982;Favero et al, 2011;Nattie & Li, 2008). All data described above are related to physiological conditions; however, in the present study, we verified that in a model of PD, there was a reduction in the number of phox2b-expressing neurons in the NTS region that could be correlated with the loss of autonomic and respiratory function (Falquetto et al, 2017;Oliveira et al, 2017;Tuppy et al, 2015). For example, we showed before that disruption of phox2b-expressing neurons in the NTS impacts the proper function of cardiovascular reflexes (Falquetto et al, 2017).…”

Blunted cardiovascular responses to exercise in Parkinson’s disease patients: role of the muscle metaboreflex

“…It is likely that Lewy bodies, an abnormal aggregates of protein that are widely distributed in the hypothalamus, sympathetic centers (intermediolateral nucleus of the thoracic cord and sympathetic ganglia), and parasympathetic centers (dorsal vagal and sacral parasympathetic nuclei) could disrupt the central component of autonomic reflex arches, which are involved in autonomic regulation (Braak and Braak 2000). Also, Falquetto et al (2017) recently showed, using an animal model of PD, that intrastriatal injection of 6-hydroxydopamine (6-OHDA) led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus tractus solitarii (NTS; i.e., the most important integrative area of cardiovascular control) (Person 1989). Altogether, the reduced number of brain stem neurons involved in cardiovascular regulation could lead to the impaired cardiovascular response to exercise observed in patients with PD.…”

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

“…Intrastriatal 6-OHDA administration leads to depletion of catecholamine-expressing neurons and a selective inhibitor of noradrenergic transporter is generally used for protection of noradrenergic neurons, but even then, to a lesser extent, 6-OHDA is still capable of damaging noradrenergic neurons (Fulceri et al 2006). This could be, at least partly, responsible for the lesions seen also in the locus coeruleus (Bonito-Oliva et al 2014) as well as within the nucleus of the solitary tract (Falquetto et al 2017) and the distinct cortical regions (Becker et al 2018), associated with both central (cognitive impairment, depression, anxiety, olfactory deficit) as well as peripheral (cardiovascular, gastrointestinal) non-motor symptoms (Bonito-Oliva et al 2014;Falquetto et al 2017;Becker et al 2018;Feng et al 2019). MPTP neurodegeneration is also not exclusively limited to the nigrostriatal region, since MPTP was shown to bind to other brain regions as well (Javitch et al 1985), and peripheral MPTP treatment was found to induce lesions in the hypothalamus (Gibb et al 1986) which were associated with anorexia manifested prior to the appearance of motor deficits (Sandyk et al 1990).…”