RESUMEN
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non-motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α-synuclein, LRRK2, DJ-1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α-synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD-like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector-mediated transgene expression and, recently, injections of misfolded α-synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre-clinical PD research towards successful disease-modifying therapy. © 2020 The Authors.
Asunto(s)
Neurotoxinas/toxicidad , Trastornos Parkinsonianos , Animales , Cuerpo Estriado/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/ultraestructura , Evaluación Preclínica de Medicamentos/métodos , Predicción , Estudio de Asociación del Genoma Completo , Técnicas Histológicas , Humanos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/genética , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Plaguicidas/toxicidad , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Ratas , Sustancia Negra/efectos de los fármacos , Sinucleinopatías/genética , Sinucleinopatías/patología , alfa-Sinucleína/biosíntesis , alfa-Sinucleína/genéticaRESUMEN
Ischemic stroke is the leading cause of disability, and effective therapeutic strategies are needed to promote complete recovery. Neuroinflammation plays a significant role in stroke pathophysiology, and there is limited understanding of how it affects recovery. The aim of this study was to characterize the spatiotemporal expression profile of microglial activation and whether dampening microglial/macrophage activation post-stroke facilitates the recovery. For dampening microglial/macrophage activation, we chose intranasal administration of naloxone, a drug that is already in clinical use for opioid overdose and is known to decrease microglia/macrophage activation. We characterized the temporal progression of microglia/macrophage activation following cortical ischemic injury in rat and found the peak activation in cortex 7 d post-stroke. Unexpectedly, there was a chronic expression of phagocytic cells in the thalamus associated with neuronal loss. (+)-Naloxone, an enantiomer that reduces microglial activation without antagonizing opioid receptors, was administered intranasally starting 1 d post-stroke and continuing for 7 d. (+)-Naloxone treatment decreased microglia/macrophage activation in the striatum and thalamus, promoted behavioral recovery during the 14-d monitoring period, and reduced neuronal death in the lesioned cortex and ipsilateral thalamus. Our results are the first to show that post-stroke intranasal (+)-naloxone administration promotes short-term functional recovery and reduces microglia/macrophage activation. Therefore, (+)-naloxone is a promising drug for the treatment of ischemic stroke, and further studies should be conducted.