Pharmacologic antagonism of dopamine receptor D3 attenuates neurodegeneration and motor impairment in a mouse model of Parkinson's disease.
Neuroinflammation involves the activation of glial cells, which is associated to the progression of neurodegeneration in Parkinson's disease. Recently, we and other researchers demonstrated that dopamine receptor D3 (D3R)-deficient mice are completely refractory to neuroinflammation and consequent neurodegeneration associated to the acute intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we examined the therapeutic potential and underlying mechanism of a D3R-selective antagonist, PG01037, in mice intoxicated with a chronic regime of administration of MPTP and probenecid (MPTPp). Biodistribution analysis indicated that intraperitoneally administered PG01037 crosses the blood-brain barrier and reaches the highest concentration in the brain 40 min after the injection. Furthermore, the drug was preferentially distributed to the brain in comparison to the plasma. Treatment of MPTPp-intoxicated mice with PG01037 (30 mg/kg, administrated twice a week for five weeks) attenuated the loss of dopaminergic neurons in the substantia nigra pars compacta, as evaluated by stereological analysis, and the loss of striatal dopaminergic terminals, as determined by densitometric analyses of tyrosine hydroxylase and dopamine transporter immunoreactivities. Accordingly, the treatment resulted in significant improvement of motor performance of injured animals. Interestingly, the therapeutic dose of PG01037 exacerbated astrogliosis and resulted in increased ramification density of microglial cells in the striatum of MPTPp-intoxicated mice. Further analyses suggested that D3R expressed in astrocytes favours a beneficial astrogliosis with anti-inflammatory consequences on microglia. Our findings indicate that D3R-antagonism exerts a therapeutic effect in parkinsonian animals by reducing the loss of dopaminergic neurons in the nigrostriatal pathway, alleviating motor impairments and modifying the pro-inflammatory phenotype of glial cells.
Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago 8370146, Chile.
Daniela
D
Elgueta
Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, 31008, Spain.
María S
MS
Aymerich
Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile.
Francisco
F
Contreras
Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile.
Andro
A
Montoya
Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.
Marta
M
Celorrio
Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain.
Estefanía
E
Rojo-Bustamante
Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile.
Eduardo
E
Riquelme
Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile.
Hugo
H
González
Department of Molecular Genetics and Microbiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, Santiago, Chile.
Mónica
M
Vásquez
Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona 08028, Spain; CIBERNED. Centro de Investigación en Red. Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28049, Madrid, Spain.
Rafael
R
Franco
Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago 8370146, Chile. Electronic address: rpacheco@cienciavida.org.
Rodrigo
R
Pacheco
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D004660:Encephalitis / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D010300:Parkinson Disease / Q000150:complications / Q000517:prevention & control; D020734:Parkinsonian Disorders / Q000150:complications / Q000517:prevention & control*; D065842:Pars Compacta / Q000187:drug effects / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001549:Benzamides; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; D018696:Neuroprotective Agents; D011725:Pyridines; D050637:Receptors, Dopamine D3
Astrocytes; Dopamine receptors; Microglia; Neuroinflammation; Parkinson's disease