27 research outputs found
Enfermedad de Parkinson
La enfermedad de Parkinson es una enfermedad neurodegenerativa progresiva que afecta, entre otros sistemas de neurotransmisores, a la proyecciĂłn nigroestriatal dopaminĂ©rgica. El tratamiento paliativo con levodopa y/o agonistas dopaminĂ©rgicos mejora la sintomatologĂa motora pero los pacientes continĂșan empeorando clĂnicamente tanto por el proceso neurodegenerativo que continĂșa actuando como el factor añadido del envejecimiento fisiolĂłgico. Estudios (in vitro e in vivo) en modelos experimentales han demostrado que los agonistas dopaminĂ©rgicos tienen efectos neuroprotectores mediados directa o indirectamente por su capacidad de estabilizaciĂłn mitocondrial, sus efectos antioxidantes, la sĂntesis de factores de crecimiento, la estabilizaciĂłn del sistema ubicuitin-proteasoma, la activaciĂłn de la autofagia, la inducciĂłn antiapoptĂłtica de la familia Bcl2 o la potenciaciĂłn de neurogĂ©nesis (proliferaciĂłn y migraciĂłn) en la Zona Sub-Ventricular (SVZ). Los estudios clĂnicos no han confirmado completamente estos efectos y son necesarios anĂĄlisis en grupos de pacientes mejor clasificados con similar sintomatologĂa clĂnica, idĂ©nticos tratamientos y mismo tiempo de evoluciĂłn. Los avances tecnolĂłgicos que permitan conocer la etiologĂa y la patogĂ©nesis de la enfermedad (genĂ©tica y ambiental) junto a mĂ©todos de evaluaciĂłn clĂnica mĂĄs fidedignos abren puertas de esperanza para desarrollar nuevas molĂ©culas en el tratamiento sintomĂĄtico de la enfermedad de Parkinson. Estas molĂ©culas deberĂĄn exhibir potencial neuroprotector (profilĂĄctico y/o terapĂ©utico) capaz de mantener la funciĂłn fisiolĂłgica cerebral, y de modificar/ ralentizar el curso natural de la enfermedad
Vision-based gait impairment analysis for aided diagnosis
Gait is a firsthand reflection of health condition. This belief has inspired recent research efforts to automate the analysis of
pathological gait, in order to assist physicians in decision-making. However, most of these efforts rely on gait descriptions
which are difficult to understand by humans, or on sensing technologies hardly available in ambulatory services. This
paper proposes a number of semantic and normalized gait features computed from a single video acquired by a low-cost
sensor. Far from being conventional spatio-temporal descriptors, features are aimed at quantifying gait impairment, such
as gait asymmetry from several perspectives or falling risk. They were designed to be invariant to frame rate and image
size, allowing cross-platform comparisons. Experiments were formulated in terms of two databases. A well-known generalpurpose
gait dataset is used to establish normal references for features, while a new database, introduced in this work,
provides samples under eight different walking styles: one normal and seven impaired patterns. A number of statistical
studies were carried out to prove the sensitivity of features at measuring the expected pathologies, providing enough evidence
about their accuracy
Parkinsonâs disease and autophagy
It is generally accepted that a correlation between neurodegenerative disease and protein aggregation in the brain exists; however, a
causal relationship has not been elucidated. In neurons, failure of autophagy may result in the accumulation of aggregate-prone
proteins and subsequent neurodegeneration. Thus, pharmacological induction of autophagy to enhance the clearance of intracytoplasmic
aggregate-prone proteins has been considered as a therapeutic strategy to ameliorate pathology in cell and animal
models of neurodegenerative disorders. However, autophagy has also been found to be a factor in the onset of these diseases, which
raises the question of whether autophagy induction is an effective therapeutic strategy, or, on the contrary, can result in cell death.
In this paper, we will first describe the autophagic machinery, and we will consider the literature to discuss the neuroprotective
effects of autophagy
7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease
Neuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS+ and Phospho-Thr34-DARPP-32+ cells, accompanied by a consequent decrease of total DARPP-32+ cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.This work was supported by grants from the Spanish Ministry of Science (SAF 2007-62262), FIS (PI/2010/02827) and CIBERNED (Centro de InvestigacioÌn BiomeÌdica en Red sobre Enfermedades Neurodegenerativas)
Octodon degus: A Model for the Cognitive Impairment Associated with Alzheimer's Disease
Octodon degus (O. degus) is a diurnal rodent that spontaneously develops several physiopathological conditions, analogous in many cases to those experienced by humans. In light of this, O. degus has recently been identified as a very valuable animal model for research in several medical fields, especially those concerned with neurodegenerative diseases in which risk is associated with ageing. O. degus spontaneously develops ÎČ-amyloid deposits analogous to those observed in some cases of Alzheimerâs disease (AD). Moreover, these deposits are thought to be the key feature for AD diagnosis, and one of the suggested causes of cell loss and cognitive deficit. This review aims to bring together information to support O. degus as a valuable model for the study of cerebral aging
Critical evaluation of the anatomical location of the Barrington nucleus: relevance for deep brain stimulation surgery of pedunculopontine tegmental nucleus
Deep brain stimulation (DBS) has become the standard surgical procedure for advanced Parkinsonâs disease (PD). Recently, the pedunculopontine tegmental nucleus (PPN) has emerged as a potential target for DBS in patients whose quality of life is compromised by freezing of gait and falls. To date, only a few groups have published their long-term clinical experience with PPN stimulation. Bearing in mind that the Barrington (Bar) nucleus and some adjacent nuclei (also known as the micturition centre) are close to the PPN and may be affected by DBS, the aim of the present study was to review the anatomical location of this structure in human and other species. To this end, the Bar nucleus area was analysed in mouse, monkey and human tissues, paying particular attention to the anatomical position in humans, where it has been largely overlooked. Results confirm that anatomical location renders the Bar nucleus susceptible to influence by the PPN DBS lead or to diffusion of electrical current. This may have an undesirable impact on the quality of life of patients
Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism
Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinsonâs disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9+ glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism
Evidence of oligodendrogliosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism
Aims: Mice and nonhuman primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigrostriatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods: We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques respectively. Oligodendrocytes were immunolabelled by cell-specific markers and analysed by confocal microscopy. Results: In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlates with the reduction in the level of dopaminergic innervation to the striatum. Conclusions: This event, associated with early damage of the dopaminergic neurone axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism
Persistent phagocytic characteristics of microglia in the substantia nigra of long-term Parkinsonian macaques
Patients with Parkinson's disease show persistent microglial activation in the areas of the brain where the degeneration of dopaminergic neurons takes place. The reason for maintaining this activated state is still unknown, but it is thought that this persistent microglial activation may contribute to the degeneration of dopaminergic neurons. In this study, we report the microanatomical details of microglia and the relationship between microglia and neurons in the substantia nigra pars compacta of Parkinsonian monkeys years after insult with MPTP. We observed that microglial cells appear polarized toward dopaminergic neurons in MPTP-treated macaques compared to untreated animals and present clear phagocytic characteristics, such as engulfing gliaptic contacts, an increase in Golgi apparatus protein machinery and ball-and-chain phagocytic buds. These results demonstrate that activated microglia maintain phagocytic characteristics years after neurotoxin insult, and phagocytosis may be a key contributor to the neurodegenerative process
ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo
The role of microglial motility in the context of adult neurodegeneration is poorly understood. In the
present work, we investigated the microanatomical details of microglia-neuron interactions in an
experimental mouse model of Parkinsonâs disease following the intraperitoneal injection of MPTP. The
specific intoxication of dopaminergic neurons induces the cellular polarization of microglia, leading to the
formation of body-to-body neuron-glia contacts, called gliapses, which precede neuron elimination.
Inhibiting ROCK/Cdc42-mediated microglial motility in vivo blocks the activating features of microglia,
such as increased cell size and number of filopodia and diminishes their phagocyting/secreting domains, as
the reduction of the Golgi apparatus and the number of microglia-neuron contacts has shown.
High-resolution confocal images and three-dimensional rendering demonstrate that microglia engulf entire
neurons at one-to-one ratio, and the microglial cell body participates in the formation of the phagocytic cup,
engulfing and eliminating neurons in areas of dopaminergic degeneration in adult mammals