Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson’s disease

Autor: Marie-Kim St-Pierre, Martin Parent, Marie-Ève Tremblay, Léo Cantin, Fernando González Ibanez, Dave Gagnon, Ifeoluwa O. Awogbindin, Mélanie Bourque, Katherine Picard, Cynthia Lecours, Maude Bordeleau, Amin Benadjal, Thérèse Di Paolo
Přispěvatelé: Gestionnaire, Hal Sorbonne Université, Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), McGill University = Université McGill [Montréal, Canada], University of Ibadan, Biologie intégrative (FRBI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Laval [Québec] (ULaval), University of Victoria [Canada] (UVIC), University of British Columbia (UBC)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Levodopa
medicine.medical_specialty
Dyskinesia
Drug-Induced
Parkinson's disease
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Immunology
03 medical and health sciences
Behavioral Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Neuroinflammation
Internal medicine
Basal ganglia
medicine
Animals
Humans
Microglia
Endocrine and Autonomic Systems
business.industry
MPTP
Putamen
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Parkinson Disease
medicine.disease
MPTP monkey model
Pathophysiology
3. Good health
nervous system diseases
Macaca fascicularis
030104 developmental biology
medicine.anatomical_structure
Endocrinology
chemistry
nervous system
Parkinson’s disease
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: Brain, Behavior, and Immunity
Brain, Behavior, and Immunity, 2020, 90, pp.81-96. ⟨10.1016/j.bbi.2020.07.044⟩
Brain, Behavior, and Immunity, Elsevier, 2020, 90, pp.81-96. ⟨10.1016/j.bbi.2020.07.044⟩
ISSN: 0889-1591
1090-2139
DOI: 10.1016/j.bbi.2020.07.044
Popis: International audience; Parkinson's disease (PD) is the most common neurodegenerative motor disorder. The mechanisms underlying the onset and progression of Levodopa (L-Dopa)-induced dyskinesia (LID) during PD treatment remain elusive. Emerging evidence implicates functional modification of microglia in the development of LID. Thus, understanding the link between microglia and the development of LID may provide the knowledge required to preserve or promote beneficial microglial functions, even during a prolonged L-Dopa treatment. To provide novel insights into microglial functional alterations in PD pathophysiology, we characterized their density, morphology, ultrastructure, and degradation activity in the sensorimotor functional territory of the putamen, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cynomolgus monkeys. A subset of MPTP monkeys was treated orally with L-Dopa and developed LID similar to PD patients. Using a combination of light, confocal and transmission electron microscopy, our quantitative analyses revealed alterations of microglial density, morphology and phagolysosomal activity following MPTP intoxication that were partially normalized with L-Dopa treatment. In particular, microglial density, cell body and arborization areas were increased in the MPTP monkeys, whereas L-Dopa-treated MPTP animals presented a microglial phenotype similar to the control animals. At the ultrastructural level, microglia did not differ between groups in their markers of cellular stress or aging. Nevertheless, microglia from the MPTP monkeys displayed reduced numbers of endosomes, compared with control animals, that remained lower after L-Dopa treatment. Microglia from MPTP monkeys treated with L-Dopa also had increased numbers of primary lysosomes compared with non-treated MPTP animals, while secondary and tertiary lysosomes remained unchanged. Moreover, a decrease microglial immunoreactivity for CD68, considered a marker of phagocytosis and lysosomal activity, was measured in the MPTP monkeys treated with L-Dopa, compared with non-treated MPTP animals. Taken together, these findings revealed significant changes in microglia during PD pathophysiology that were partially rescued by L-Dopa treatment. Albeit, this L-Dopa treatment conferred phagolysosomal insufficiency on microglia in the dyskinetic Parkinsonian monkeys.
Databáze: OpenAIRE
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