Pharmacologic antagonism of dopamine receptor D3 attenuates neurodegeneration and motor impairment in a mouse model of Parkinson's disease
Autor: | Marta Celorrio, Rodrigo Pacheco, Estefanía Rojo-Bustamante, Daniela Elgueta, Rafael Franco, Hugo González, Francisco Contreras, María S. Aymerich, Andro Montoya, Mónica Vásquez, Eduardo Riquelme |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Pyridines Nigrostriatal pathway Substantia nigra Pharmacology Motor Activity 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Mice 0302 clinical medicine Parkinsonian Disorders medicine Animals Pars Compacta Neuroinflammation Dopamine transporter biology Pars compacta business.industry MPTP Dopaminergic Neurons Dopaminergic Receptors Dopamine D3 Parkinson Disease medicine.disease Corpus Striatum Astrogliosis Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Neuroprotective Agents nervous system chemistry Astrocytes Benzamides biology.protein Encephalitis Microglia business Neuroscience 030217 neurology & neurosurgery |
Zdroj: | Neuropharmacology. 113 |
ISSN: | 1873-7064 |
Popis: | 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. |
Databáze: | OpenAIRE |
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