Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia. (1st January 2020)

• Record Type: Journal Article
• Authors: Vaz, Rita L.; Chapela, Diana; Coelho, Joana E.; Lopes, Luísa V.; Ferreira, Joaquim J.; Afonso, Nuno D.; Sousa, Sara; Outeiro, Tiago F.
• Is Part Of: Neuroscience. Volume 424(2020)
• Page Start: 58
• Page End: 71
• Publication Date: 2020-01-01
• Subjects: 6-OHDA 6-hydroxydopamine -- AIMs abnormal involuntary movements -- DA dopamine -- DAT dopamine transporter -- FoG freezing of gait -- i.p. intraperitoneal -- L-dopa levodopa -- LID L-dopa induced dyskinesia -- MOR µ-opioid receptor -- NET norepinephrine transporter -- PBS phosphate buffer saline -- PFA paraformaldehyde -- SNpc substantia nigra pars compacta -- STR striatum -- TBS trizma buffer saline -- TH tyrosine hydroxylase -- VTA ventral tegmental area; levodopa-induced dyskinesia -- µ-opioid receptor agonist -- mouse -- norepinephrine reuptake inhibitor -- Parkinson's disease -- tapentadol; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.08.046
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: The antiparkinsonian properties of tapentadol are assessed in a mouse model of PD. 6-OHDA-lesioned mice are submitted to chronic treatment with tapentadol and L-dopa. Tapentadol halts the aggravation of AIMs when administered with L-dopa. Dyskinetic mice exhibit motor impairments during L-dopa OFF state. Tapentadol improves motor performance during L-dopa OFF state. Abstract: The motor features in Parkinson's disease (PD) are associated with the degeneration of dopaminergic cells in the substantia nigra in the brain. Thus, the gold-standard in PD therapeutics still consists of dopamine replacement with levodopa. However, as the disease progresses, this therapeutic option becomes less effective and can be accompanied by levodopa-induced complications. On the other hand, several other neuronal pathways have been implicated in the pathological mechanisms of PD. In this context, the development of alternative therapeutic options that modulate non-dopaminergic targets is emerging as a major goal in the field. In a phenotypic-based screen in a zebrafish model of PD, we identified tapentadol as a candidate molecule for PD. The therapeutic potential of an agent that modulates the opioid and noradrenergic systems has not been explored, despite the implication of both neuronal pathways in parkinsonism. Therefore, we assessed the therapeutic properties of this µ-opioid receptor agonist and norepinephrine reuptake inhibitor in the 6-hydroxydopamine mouse model of parkinsonism. We further submitted 6-hydroxydopamine-lesioned mice to chronic treatment with levodopa and evaluated the effects of tapentadol during levodopa OFF states and on levodopa-induced dyskinesia. Importantly, we found that tapentadol halted the aggravation of dyskinesia and improved the motor impairments during levodopa OFF states. Altogether, our findings raise the hypothesis that concomitant modulation of µ-opioid receptor and norepinephrine transporter might constitute relevant intervention strategies in PD and that tapentadol holds therapeutic potential that may be translated into the clinical practice.