Els processos neuroinflamatoris associats a les malalties neurodegeneratives. Si se m’inflama el cervell, se m’oblida el teu nom?

Aquest assaig és una revisió sobre els processos neuroinflamatoris que esdevenen en les malalties neurodegeneratives. Es descriuen les diferents estructures cel·lulars que trobem en el sistema nerviós, i farem especial èmfasi en les cèl·lules de micròglia. Enunciarem breument què se sap sobre l’associació entre aquests processos inflamatoris i diferents malalties com ara la malaltia d’Alzheimer, la malaltia de Parkinson i la malaltia de Huntington. Estudis clínics han intentat associar l’ús d’antiinflamatoris amb la prevenció o alentiment d’aquestes malalties neurodegeneratives, sense que els resultats hagen estat suficientment concloents. Davant l’escàs èxit d’aquest abordatge, s’analitzarà finalment la nova possibilitat d’introduir teràpies immunomoduladores dels processos inflamatoris en aquestes malalties neurodegeneratives.This article provides an overview of the neuroinflammatory processes that occur in neurodegenerative diseases. The different cell structures found in the nervous system are described, with special emphasis on microglia cells. This is followed by a brief review of what is currently known about the link between these inflammatory processes and various diseases such as Alzheimer’s, Parkinson’s and Huntington’s. Some clinical studies have attempted to establish whether the use of anti-inflammatory drugs can prevent or slow down these neurodegenerative diseases, but results have not been sufficiently conclusive. Finally, given the lack of success of this approach, the possibility of developing new immunomodulatory therapies for the treatment of inflammatory processes associated with these neurodegenerative diseases is discussed.Este ensayo es una revisión de los procesos neuroniflamatorios que ocurren en las enfermedades neurodegenerativas. Se describen las diferentes estructuras celulares que encontramos en el sistema nervioso, con especial énfasis en las células de la microglia. Se repasa brevemente lo que se sabe sobre la asociación entre estos procesos inflamatorios u diferentes enfermedades como la enfermedad de Alzhéimer, la enfermedad de Parkinson y la enfermedad de Huntington. Estudios clínicos han intentado asociar el uso de antiinflamatorios con la prevención o alineamiento de estas enfermedades neurodegenerativas, sin que los resultados hayan estado suficientemente concluyentes. Frente al escaso éxito de este abordaje, se analiza finalmente la nueva posibilidad de introducir terapias inmunomoduladoras de los procesos inflamatorios en estas enfermedades neurodegenerativas

Eficacia analgésica del tratamiento invasivo miofascial (punción seca) en fibromialgia

Introducción. La fibromialgia (FM) es una entidad clínica caracterizada por un dolorcrónico generalizado. La sensibilización central del sistema nervioso se considera laexplicación más plausible al dolor crónico generalizado que afecta a las personas conFM. La nueva neurobiología del dolor establece que los puntos gatillo miofascialespuede ser fuente periférica capaz de originar el dolor. El tratamiento de los PGM puededisminuir el dolor de los pacientes con FM. Metodología. Se realizó un ensayo clínicoaleatorizado con 120 participantes, se diseñaron 3 grupos con el objetivo de comprobarla eficacia de la intervención. Resultados. Los resultados obtenidos determinandiferencias significativas entre el grupo Tratamiento y grupo Placebo (p=0,01). Conclusiones.Los pacientes sometidos a la técnica de punción seca mostraron una disminuciónde la hiperalgesia local a las 24 horas de la intervención.Introduction. Fibromyalgia (FM) is a clinical entity characterized by widespread chronicpain. Central sensitization of the nervous system is considered the most plausibleexplanation for the widespread chronic pain that affects people with FM. The new neurobiologyof pain states that myofascial trigger points can be a peripheral source capableof causing pain. Treatment of MTrPs may decrease the pain of patients with FM.Methodology. We designed a randomized clinical trial with 120 participants dividedinto 3 groups with the objective of checking the effectiveness of the intervention. Results.The results obtained determined significant differences between the treatmentand the Placebo group (p = 0.006). Conclusions. Patients undergoing the dry needlingtechnique showed a decrease in local hyperalgesia 24 hours after surgery

Implications of glial nitric oxide in neurodegenerative diseases

Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases

MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes.

The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes

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 Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)

Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer´s disease

Neuroinflammation and insulin resistance in the brain are intimately linked to neurodegenerative disorders, including Alzheimer’s disease. Even though traditionally Alzheimer´s disease has been associated to Aβ deposits and hyperphosphorylated Tau intracellular tangles, several studies show that neuroinflammation may be the initial cause that triggers degeneration. Accordingly, a number of natural supplements that improves brain insulin sensitivity and reduce neuroinflammation have been proposed as good choices in the therapeutic prevention of cognitive decline. Further supporting this evidence, we show that phytohormone Abscisic Acid, can prevent memory impairment and neuroinflammation markers in a triple transgenic mouse model, where no peripheral inflammatory changes have occurred. Moreover, our data strongly suggests that early intervention is critical for good prognosis, and that cognitive improvement requires longer treatment than recovering neuroinflammation markers

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

Modulation of forebrain function by nucleus incertus and relaxin-3/RXFP3 signaling

This is the pre-peer reviewed version of the following article: Modulation of forebrain function by nucleus incertus and relaxin‐3/RXFP3 signaling, CNS neuroscience & therapeutics, 2018, vol. 24, no 8, p. 694-702, which has been published in final form at https://doi.org/10.1111/cns.12862. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.The nucleus incertus (NI) in the pontine tegmentum sends ascending projections to the midbrain, hypothalamus, amygdala, basal forebrain, hippocampus, and prefrontal cortex, and has a postulated role in modulating several forebrain functions. A substantial population of GABAergic NI neurons expresses the neuropeptide, relaxin‐3, which acts via the Gi/o‐protein‐coupled receptor, RXFP3, present throughout the forebrain target regions. Broad and specific manipulations of these systems by activation or inhibition of the NI or modulating RXFP3 signaling have revealed key insights into the likely influence of the NI/relaxin‐3/RXFP3 system on modalities including arousal, feeding, stress responses, anxiety and addiction, and attention and memory. This range of actions corresponds to a likely impact of NI/(relaxin‐3) projections on multiple integrated circuits, but makes it difficult to draw conclusions about a generalized function for this network. This review will focus on the key physiological process of oscillatory theta rhythm and the neural circuits that promote it during behavioral activation, highlighting the ability of NI and relaxin‐3/RXFP3 signaling systems to modulate these circuits. A better understanding of these mechanisms may provide a way to therapeutically adjust malfunction of forebrain activity present in several pathological conditions

CCL2-Expressing Astrocytes Mediate the Extravasation of T Lymphocytes in the Brain. Evidence from Patients with Glioma and Experimental Models In Vivo

CCL2 is a chemokine involved in brain inflammation, but the way in which it contributes to the entrance of lymphocytes in the parenchyma is unclear. Imaging of the cell type responsible for this task and details on how the process takes place in vivo remain elusive. Herein, we analyze the cell type that overexpresses CCL2 in multiple scenarios of T-cell infiltration in the brain and in three different species. We observe that CCL2+ astrocytes play a part in the infiltration of T-cells in the brain and our analysis shows that the contact of T-cells with perivascular astrocytes occurs, suggesting that may be an important event for lymphocyte extravasation

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