Stimulation of noradrenergic transmission by reboxetine is beneficial for a mouse model of progressive parkinsonism

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by motor deficits such as tremor, rigidity and bradykinesia. These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD. Postmortem studies of brains from PD patients have revealed the degeneration of noradrenergic neurons in the locus coeruleus (LC) to the same or even greater extent than that observed in the dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA). Moreover, studies performed on rodent models suggest that enhancement of noradrenergic transmission may attenuate the PD-like phenotype induced by MPTP administration, a neurotoxin-based PD model. The aim of this study was to investigate whether chronic treatment with either of two compounds targeting the noradrenergic system (reboxetine or atipamezole) possess the ability to reduce the progression of a PD-like phenotype in a novel mouse model of progressive dopaminergic neurodegeneration induced by the genetic inhibition of rRNA synthesis in dopaminergic neurons, mimicking a PD-like phenotype. The results showed that reboxetine improved the parkinsonian phenotype associated with delayed progression of SN/VTA dopaminergic neurodegeneration and higher dopamine content in the striatum. Moreover, the alpha1-adrenergic agonist phenylephrine enhanced survival of TH+ neurons in primary cell cultures, supporting the putative neuroprotective effects of noradrenergic stimulation. Our results provide new insights regarding the possible influence of the noradrenergic system on dopaminergic neuron survival and strongly support the hypothesis regarding the neuroprotective role of noradrenaline.

Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite—Urolithin A—In the Brain

“…Given the fact that loss of dopaminergic neurons triggers deregulation of motor symptoms [36], which we had previously demonstrated in an inducible transgenic PD model [37], we performed both the microscopic examination and the immunofluorescent analysis of TH+ neurons in sections of the SN area, which is the region of interest in experimental PD models due to the vulnerability of dopaminergic neurons in the brain [38]. In agreement with the other authors' findings [39,40], a microscopic examination proved that rotenone-induced neurotoxicity involved the midbrain, while sections of cerebellum and cortex showed a quite normal structure.…”

The Noradrenergic System in Parkinson’s Disease

“…Conversely, the damage produced by MPTP is reduced when the synthesis of NA is boosted (Kilbourn et al, 1998;Archer, 2016) or the NET is knocked out (Rommelfanger et al, 2004). A recent publication using mutant mice characterized by the progressive degeneration of dopaminergic neurons demonstrated that chronic pharmacological NET blockade ameliorates such degeneration and the subsequent motor impairment (Kreiner et al, 2019). Peripheral administration of the NET blocker atomoxetine also reduced DA damage in a lipopolysaccharide inflammatory rat model of PD (Yssel et al, 2018).…”

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…In contrast to PD patients and toxin‐induced mouse PD models, nucleolar integrity was not affected by DJ‐1/PINK1 double knockout, highlighting the value of the TIF‐IA conditional knockout model to study PD‐related nucleolar dysfunction (Evsyukov et al., ). The utility of TIF‐IA/DAT‐CreET2 mice for pre‐clinical drug testing has recently been proven by the study showing a neuroprotective effect of reboxetine, a selective noradrenaline reuptake inhibitor, on dopaminergic neurons (Kreiner et al., ). These mice have also been used to demonstrate the neuroprotective outcome of Akt pathway activation in adult dopaminergic neurons (Domanskyi et al., ).…”