Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

A. Stojakovic, G. Paz-Filho, M. Arcos-Burgos, J. Licinio, M.-L. Wong, C.A. Mastronardi

Resultado de la investigación: Contribución a RevistaArtículo

6 Citas (Scopus)

Resumen

Resumen
La interleucina-1 (IL-1), una citoquina proinflamatoria sintetizada y liberada por microglia activada, puede causar neurodegeneración dopaminérgica que conduce a la enfermedad de Parkinson (EP). Sin embargo, es incierto si la IL-1 puede actuar directamente o exacerbando las acciones dañinas de otros insultos cerebrales. Para determinar el papel de la vía IL-1 en la neurodegeneración dopaminérgica y las habilidades motoras durante el envejecimiento, se comparó a ratones con un deterioro[knockout de la caspasa-1 (caspase-1-/-)] o una actividad sobreactivada de la IL-1[knockout del antagonista del receptor de la IL-1 (IL-1ra-/-)] con ratones de tipo salvaje (wt) a una edad joven y mediana. Sus habilidades motoras fueron evaluadas por las pruebas de campo abierto y rotarodales, y la cuantificación de sus neuronas dopaminérgicas y microglia activada dentro de la sustancia negra fue realizada por inmunohistoquímica. Los ratones IL-1ra-/- mostraron una disminución en las habilidades motoras relacionada con la edad, un número reducido de neuronas dopaminérgicas y un aumento en la microglia activada en comparación con los ratones wt o casp1-/-. Los ratones Casp1-/- tuvieron cambios similares en las habilidades motoras y en las neuronas de la dopamina, pero menos células de microglia activadas que los ratones wt. Nuestros resultados sugieren que la vía IL-1 sobreactivada que se da en ratones con IL-1ra-/- en ausencia de intervenciones inflamatorias (p.ej., inyecciones intracerebrales realizadas en modelos animales de EP) aumenta la activación de los microglios, disminuye el número de neuronas dopaminérgicas y reduce sus habilidades motoras. La disminución de la actividad de la IL-1 en ratones casp1-/- no produjo efectos protectores claros en comparación con los ratones wt. En resumen, en ausencia de insultos cerebrales manifiestos, la activación crónica de la vía IL-1 puede promover aspectos patológicos de la EP per se, pero su deterioro no parece producir ventajas sobre los ratones con peso.
Idioma originalEnglish (US)
Páginas (desde-hasta)4486-4495
Número de páginas10
PublicaciónMolecular Neurobiology
Volumen54
N.º6
DOI
EstadoPublished - jun 29 2016

Huella dactilar

Interleukin-1
Motor Skills
Microglia
Dopaminergic Neurons
Interleukin 1 Receptor Antagonist Protein
Parkinson Disease
Rotarod Performance Test
Caspase 1
Interleukin-1 Receptors
Brain
Motor Neurons
Substantia Nigra
Animal Models
Immunohistochemistry
Cytokines
Injections

Citar esto

Stojakovic, A. ; Paz-Filho, G. ; Arcos-Burgos, M. ; Licinio, J. ; Wong, M.-L. ; Mastronardi, C.A. / Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement. En: Molecular Neurobiology. 2016 ; Vol. 54, N.º 6. pp. 4486-4495.
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title = "Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement",
abstract = "Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson’s disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1−/−)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra−/−)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra−/− mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1−/− mice. Casp1−/− mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra−/− mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1−/− mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice. {\circledC} 2016, The Author(s).",
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Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement. / Stojakovic, A.; Paz-Filho, G.; Arcos-Burgos, M.; Licinio, J.; Wong, M.-L.; Mastronardi, C.A.

En: Molecular Neurobiology, Vol. 54, N.º 6, 29.06.2016, p. 4486-4495.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

AU - Stojakovic, A.

AU - Paz-Filho, G.

AU - Arcos-Burgos, M.

AU - Licinio, J.

AU - Wong, M.-L.

AU - Mastronardi, C.A.

N1 - Cited By :1 Export Date: 4 April 2018 CODEN: MONBE

PY - 2016/6/29

Y1 - 2016/6/29

N2 - Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson’s disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1−/−)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra−/−)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra−/− mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1−/− mice. Casp1−/− mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra−/− mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1−/− mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice. © 2016, The Author(s).

AB - Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson’s disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1−/−)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra−/−)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra−/− mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1−/− mice. Casp1−/− mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra−/− mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1−/− mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice. © 2016, The Author(s).

U2 - 10.1007/s12035-016-9988-x

DO - 10.1007/s12035-016-9988-x

M3 - Article

VL - 54

SP - 4486

EP - 4495

JO - Molecular Neurobiology

JF - Molecular Neurobiology

SN - 0893-7648

IS - 6

ER -