Parkinson's disease-derived α-synuclein assemblies combined with chronic-type inflammatory cues promote a neurotoxic microglial phenotype.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the aggregation of α-Synuclein (αSYN) building up intraneuronal inclusions termed Lewy pathology. Mounting evidence suggests that neuron-released αSYN aggregates could be central to microglial activation, which in turn mounts and orchestrates neuroinflammatory processes potentially harmful to neurons. Therefore, understanding the mechanisms that drive microglial cell activation, polarization and function in PD might have important therapeutic implications.

A miniaturized genotoxicity evaluation system for fast biomaterial-related risk assessment.

Implants and prostheses are widely used to either repair damaged tissues or treat different diseases. Before an implant reaches the market, multiple preclinical and clinical tests must be performed. Along with cytotoxicity or hemocompatibility preclinical tests, genotoxicity is an essential feature to investigate.

Droplet-based microfluidics platform for antifungal analysis against filamentous fungi.

Fungicides are extensively used in agriculture to control fungal pathogens which are responsible for significant economic impact on plant yield and quality. The conventional antifungal screening techniques, such as water agar and 96-well plates, are based on laborious protocols and bulk analysis, restricting the analysis at the single spore level and are time consuming. In this study, we present a droplet-based microfluidic platform that enables antifungal analysis of single spores of filamentous fungus Alternaria alternata.

Rifampicin and Its Derivative Rifampicin Quinone Reduce Microglial Inflammatory Responses and Neurodegeneration Induced In Vitro by α-Synuclein Fibrillary Aggregates.

Aggregated forms of the synaptic protein α-synuclein (αS) have been proposed to operate as a molecular trigger for microglial inflammatory processes and neurodegeneration in Parkinson´s disease. Here, we used brain microglial cell cultures activated by fibrillary forms of recombinant human αS to assess the anti-inflammatory and neuroprotective activities of the antibiotic rifampicin (Rif) and its autoxidation product rifampicin quinone (RifQ). Pretreatments with Rif and RifQ reduced the secretion of prototypical inflammatory cytokines (TNF-, IL-6) and the burst of oxidative stress in microglial cells activated with αS fibrillary aggregates.

Microglial glutamate release evoked by α-synuclein aggregates is prevented by dopamine.

When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α-Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of αS but not with the native monomeric protein.

Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors.

The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms. Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD.

Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop.

Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss-of-function mutations of PARK2 and PARK6, encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early-onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways.

Exploiting the therapeutic potential of ready-to-use drugs: Repurposing antibiotics against amyloid aggregation in neurodegenerative diseases.

Neurodegenerative diseases are chronic and progressive disorders that affect specific regions of the brain, causing gradual disability and suffering that results in a complete inability of patients to perform daily functions. Amyloid aggregation of specific proteins is the most common biological event that is responsible for neuronal death and neurodegeneration in various neurodegenerative diseases. Therapeutic agents capable of interfering with the abnormal aggregation are required, but traditional drug discovery has fallen short.

Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species.

Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation.

Identification of a Novel 1,4,8-Triazaphenanthrene Derivative as a Neuroprotectant for Dopamine Neurons Vulnerable in Parkinson's Disease.

Parkinson's disease (PD) is a chronic degenerative disorder characterized by typical motor symptoms caused by the death of dopamine (DA) neurons in the midbrain and ensuing shortage of DA in the striatum, at the level of nerve terminals. No curative treatment is presently available for PD in clinical practice. In our search for neuroprotectants in PD, we generated new 1,4,8-triazaphenanthrenes by combining 6-endo-dig-cycloisomerization of propargylquinoxalines and Suzuki or Sonogashira cross-coupling reactions.

A simplified approach for efficient isolation of functional microglial cells: Application for modeling neuroinflammatory responses in vitro.

Purified microglial cells in culture are frequently used to model brain inflammatory responses but obtaining large yields of these cells on a routine basis can be quite challenging. Here, we demonstrate that it is possible to achieve high-yield isolation of pure microglial (MAC-1(+) /Fcrls(+) /Ccr2(-) ) cells from postnatal brain tissue through a simple culture procedure that mainly relies on the adhesion preference of these cells to the polycation polyethyleneimine (PEI) in serum-supplemented DMEM medium. Accordingly, other synthetic or biological substrates failed to mimic PEI effects under the same culture conditions.

New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.

Parkinson's disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c).

Doxycycline Suppresses Microglial Activation by Inhibiting the p38 MAPK and NF-kB Signaling Pathways.

In neurodegenerative diseases, the inflammatory response is mediated by activated glial cells, mainly microglia, which are the resident immune cells of the central nervous system. Activated microglial cells release proinflammatory mediators and neurotoxic factors that are suspected to cause or exacerbate these diseases. We recently demonstrated that doxycycline protects substantia nigra dopaminergic neurons in an animal model of Parkinson's disease.

HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology.

Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. In Alzheimer's disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimer's disease and related tauopathies.

Self-evolving oxidative stress with identifiable pre- and postmitochondrial phases in PC12 cells.

During the neurodegenerative process in several brain diseases, oxidative stress is known to play important roles in disease severity and evolution. Although early events of stress, such as increased lipid peroxidation and decreased superoxide dismutase, are known to characterize early onsets of these diseases, little is known about the events that participate in maintaining the chronic evolving phase influencing the disease progression in neurons. Here, we used differentiated PC12 cells to identify premitochondrial and postmitochondrial events occurring during the oxidative stress cascade leading to apoptosis.

Glycosaminoglycans, protein aggregation and neurodegeneration.

A number of neurodegenerative diseases, as Parkinson, prion, and Alzheimer's diseases, has been directly associated with altered conformations of certain peptides or proteins that assemble to form highly organized aggregates, also called amyloid fibers. Glycosaminoglycans have shown to play important roles on fibrils formation, stability and resistance to proteolysis. This manuscript reviews from basic concepts on the biochemistry and biology of glycosaminoglycans to their implications in neurodegeneration with particular emphasis in pathologic protein aggregation.