RESUMEN
Neuroinflammation contributes to neuronal degeneration in Parkinson's disease (PD). However, how brain inflammatory factors mediate the progression of neurodegeneration is still poorly understood. Experimental models of PD have shed light on the understanding of this phenomenon, but the exploration of inflammation-driven models is necessary to better characterize this aspect of the disorder. The use of lipopolysaccharide (LPS) to induce a neuroinflammation-mediated neuronal loss is useful to induce reliable elimination of dopaminergic neurons. Nevertheless, how this model parallels the PD-like neuroinflammation is uncertain. In the present work, we used the direct LPS injection as a model inductor to eliminate dopaminergic neurons of the substantia nigra pars compacta (SNpc) in rats and reevaluated the inflammatory reaction. High-resolution 3D histological examination revealed that, although LPS induced a reliable elimination of SNpc dopaminergic neurons, it also generated a massive inflammatory response. This inflammation-mediated injury was characterized by corralling, a damaged parenchyma occupied by a vast population of lesion-associated microglia and macrophages (LAMMs) undertaking wound compaction and scar formation, surrounded by highly reactive astrocytes. LAMMs tiled the entire lesion and engaged in long-standing phagocytic activity to resolve the injury. Additionally, modeling LPS inflammation in a cell culture system helped to understand the role of phagocytosis and cytotoxicity in the initial phases of dopaminergic degeneration and indicated that LAMM-mediated toxicity and phagocytosis coexist during LPS-mediated dopaminergic elimination. However, this type of severe inflammatory-mediated injury, and subsequent resolution appear to be different from the ageing-related PD scenario where the architectural structure of the parenchyma is mostly preserved. Thus, the necessity to explore new experimental models to properly mimic the inflammatory compound observed in PD degeneration.
Asunto(s)
Microglía , Enfermedad de Parkinson , Animales , Dopamina , Inflamación/metabolismo , Lipopolisacáridos/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/metabolismo , Microglía/metabolismo , Enfermedad de Parkinson/patología , Fagocitosis , Ratas , Sustancia Negra/metabolismo , Cicatrización de HeridasRESUMEN
El neurotóxico 6-hidroxidopamina (6-OHDA) ha sido utilizado para generar modelos de la enfermedad de Parkinson (EP). A la fecha se ha establecido que si bien el modelo neurodegenerativo inducido por la 6-OHDA no reproduce la totalidad de síntomas de la enfermedad, sí replica procesos celulares tales como el estrés oxidativo, la neurodegeneración, la neuroinflamación y la muerte neuronal por apoptosis. En esta revisión se contempla el análisis de los factores que influyen en la vulnerabilidad de las neuronas dopaminérgicas, así como la estrecha relación entre el proceso neurodegenerativo, el neuroinflamatorio y la apoptosis ocasionada por la 6-OHDA. El conocimiento de los mecanismos involucrados en la neurodegeneración y la muerte celular en este modelo es relevante para definir posibles blancos terapéuticos para EP (AU)
The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to induce models of Parkinson's disease (PD). We now know that the model induced by 6-OHDA does not include all PD symptoms, although it does reproduce the main cellular processes involved in PD, such as oxidative stress, neurodegeneration, neuroinflammation, and neuronal death by apoptosis. In this review we analyse the factors affecting the vulnerability of dopaminergic neurons as well as the close relationships between neuroinflammation, neurodegeneration, and apoptosis in the 6-OHDA model. Knowledge of the mechanisms involved in neurodegeneration and cell death in this model is the key to identifying potential therapeutic targets for PD (AU)
Asunto(s)
Animales , Enfermedad de Parkinson/fisiopatología , Oxidopamina/farmacocinética , Neurotoxinas/farmacocinética , Modelos Animales de Enfermedad , Apoptosis , Degeneración Estriatonigral/inducido químicamente , Estrés Oxidativo/fisiologíaRESUMEN
The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to induce models of Parkinson's disease (PD). We now know that the model induced by 6-OHDA does not include all PD symptoms, although it does reproduce the main cellular processes involved in PD, such as oxidative stress, neurodegeneration, neuroinflammation, and neuronal death by apoptosis. In this review we analyse the factors affecting the vulnerability of dopaminergic neurons as well as the close relationships between neuroinflammation, neurodegeneration, and apoptosis in the 6-OHDA model. Knowledge of the mechanisms involved in neurodegeneration and cell death in this model is the key to identifying potential therapeutic targets for PD.