1,721,091 research outputs found
Neurodegenerative Disease: What Potential Therapeutic Role of Acid-Sensing Ion Channels?
Full text linkAcidic pH shift occurs in many physiological neuronal activities such as synaptic transmission and synaptic plasticity but also represents a characteristic feature of many pathological conditions including inflammation and ischemia. Neuroinflammation is a complex process that occurs in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Acid-sensing ion channels (ASICs) represent a widely expressed pH sensor in the brain that play a key role in neuroinflammation. On this basis, acid-sensing ion channel blockers are able to exert neuroprotective effects in different neurodegenerative diseases. In this review, we discuss the multifaceted roles of ASICs in brain physiology and pathology and highlight ASIC1a as a potential pharmacological target in neurodegenerative diseases
[The treatment for Fabry disease: focus on agalsidase alpha and beta]
No full text: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme α-galactosidase A (α-Gal A), with consequent accumulation of globotrioasoylceramide in cells and tissues of the body, resulting in a multi-system pathology. Classically affected hemizygous males may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), and cerebrovascular (transient ischemic attacks, strokes) signs of the disease, while heterozygous females have symptoms ranging from very mild to severe. End-stage renal disease and cardiovascular or cerebrovascular complications limit life-expectancy of untreated patients. Demonstration of α-Gal A deficiency is the definitive method for the diagnosis of hemizygous males, while it's often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. The treatment options for FD are enzyme replacement therapy (ERT), and the oral pharmacological chaperone migalastat. Two different products, agalsidase alfa and agalsidase beta, have been commercially available in Europe for 20 years and they are both indicated for long-term ERT. In fact, clinical trials, observational studies and registry data have provided abundant evidence for the safety and efficacy of ERT in improving symptoms and disease progression. Agalsidase alpha and beta are two almost identical recombinant proteins although they are used clinically with a different dosage regimen. In this chapter we aim to clarify the differences between the two ERTs and how these can affect the pharmacokinetic/pharmacodynamic (PK/PD) characteristics and ultimately the risk/benefit profile. The chaperone migalastat, available in Europe since 2016, is the only oral treatment for FD, and acts stabilizing specific mutant forms of α-Gal, defined "amenable" to migalastat. A multitude of therapies are now under investigation in various phases of clinical trials. These include pegylated form of α-Gal (pegunigalsidase alpha), gene therapy (both in-vivo and ex-vivo methods), mRNA therapy (inducing production of α-Gal) and substrate reduction therapy (inhibitors of glucosylceramide synthase leading to reduction of Gb-3)
Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy
Full text linkNovel effective therapeutic strategies are needed to treat brain neurodegenerative diseases and to improve the quality of life of patients affected by Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral sclerosis (ALS) as well as other brain conditions. At present no effective treatment options are available; current therapeutics for neurodegenerative diseases (NDs) improve cognitive symptoms only transiently and in a minor number of patients. Further, most of the amyloid-based phase III clinical trials recently failed in AD, in spite of promising preclinical and phase I-II clinical trials, further pinpointing the need for a better knowledge of the early mechanisms of disease as well as of more effective routes of drug administration. In fact, beyond common pathological events and molecular substrates, each of these diseases preferentially affect defined subpopulations of neurons in specific neuronal circuits (selective neuronal vulnerability), leading to the typical age-related clinical profile. In this perspective, key to successful drug discovery is a robust and reproducible biological validation of potential new molecular targets together with a concomitant set up of protocols/tools for efficient and targeted brain delivery to a specific area of interest. Here we propose and discuss Focused UltraSound aided drug administration as a specific and novel technical approach to achieve optimal concentration of the drug at the target area of interest. We will focus on drug delivery to the brain through the nasal route coupled to FUS as a promising approach to achieve neuroprotection and rescue of cognitive decline in several NDs
Editorial: Neurotrophins Biodelivery to CNS: Innovative Approaches for Disease-Modifying Therapy
Full text linkPolyvinyl butyral-based composites with carbon nanotubes: Efficient dispersion as a key to high mechanical properties
Full text linkEven if the carbon nanotubes (CNTs) and their derivatives are commonly used as reinforcing phase in composite materials, also in commercial products, their tendency to agglomerate generally determines a scarce dispersion, thus not maximizing the effect due to the second phase. In this article, a perfect dispersion of highly entangled nanotubes was achieved by using a very simple approach: exploiting the dispersing effect of a low-cost polymer, polyvinyl butyral (PVB), coupled with standard ultrasound sonication. Several dispersion approaches were tested in order to develop a consistent and widely applicable dispersion protocol. The tape casting technology was subsequently used to produce 100 to 300 μm thick PVB-matrix composite tapes, reinforced by multiwall CNTs dispersed according to the optimized protocol. Their mechanical properties were evaluated, and a simple model was used to demonstrate that the effective dispersion of CNTs is the key to obtain significantly improved properties
Targeting microglia‐synapse interactions in alzheimer’s disease
No full textIn this review, we focus on the emerging roles of microglia in the brain, with particular attention to synaptic plasticity in health and disease. We present evidence that ramified microglia, classically believed to be “resting” (i.e., inactive), are instead strongly implicated in dynamic and plastic processes. Indeed, there is an intimate relationship between microglia and neurons at syn-apses which modulates activity‐dependent functional and structural plasticity through the release of cytokines and growth factors. These roles are indispensable to brain development and cognitive function. Therefore, approaches aimed at maintaining the ramified state of microglia might be crit-ical to ensure normal synaptic plasticity and cognition. On the other hand, inflammatory signals associated with Alzheimer’s disease are able to modify the ramified morphology of microglia, thus leading to synapse loss and dysfunction, as well as cognitive impairment. In this context, we high-light microglial TREM2 and CSF1R as emerging targets for disease‐modifying therapy in Alz-heimer’s disease (AD) and other neurodegenerative disorders
Functionalization as a way to enhance dispersion of carbon nanotubes in matrices: a review
Full text linkThe past 3 decades of thorough scientific scrutiny of carbon nanotubes (CNTs) revealed that, in spite of their remarkable properties, some technological applications are adversely affected by certain difficulties in handling the CNTs, along with their tendencies, arising out of their graphitic structure, to form agglomerates and exhibit limited interaction with other materials. These issues play a crucial role when CNTs are applied as nanofillers inside matrices, in particular polar ones. In this case, unless several preliminary steps are taken, an efficient and uniform dispersion of the CNTs becomes impossible, thus the nanocomposite cannot exhibit the expected final properties. Unfortunately, a universal procedure does not exist since the problem of the dispersion of CNTs is very complex, and its solution requires an advanced understanding of the properties of the CNTs (e.g. whether the CNTs are single- or multiwalled, size, length, lattice defects etc.) as well as of the matrices used. This review aims to help the reader to select the appropriate dispersion procedure by acquiring fundamental knowledge regarding: (1) the synthesis and properties of pristine CNTs; (2) methods of chemical functionalization and properties of functionalized CNTs; and (3) methodologies for the mechanical dispersion of CNTs. A brief overview regarding chemo-physical characterization techniques is also given to enable a better evaluation of the properties of the CNTs, both before and after functionalization
Chitosan and its char as fillers in cement-base composites: A case study
Full text linkThe continuous research of new functional materials combining both advanced properties and increased sustainability has dramatically risen up in the last decades. Instead of searching for new solutions, composites (formed by a combination of already present materials) are subject of different studies due to their capability of merging the advantages of components. Hence, chitosan, a biowaste-derived biopolymer, has been thermally-converted into chars by pyrolysis treatment. Subsequently, both chitosan and its char are introduced into cementitious matrix forming cement-based composites. The analysis of the mechanical properties of these materials evidenced that char-containing composites show an incipient fracture toughness capability, very appealing for possible structural applications
Ordinal Rank and the Structure of Ability Peer Effects
Full text linkExposure to high-ability peers entails positive learning externalities, but it also decreases students’ academic self-concept because of lower ordinal ability rank. We show that, as a result, the linear-in-means parameter identifies a composite (i.e., reduced form) effect. We illustrate the empirical relevance of this issue using data from two experiments that randomly assign students to groups. We find that the structural effect of mean peer ability estimated by a model that includes rank is much larger than the reduced form effect obtained when rank is omitted. This finding also holds in non-linear and heterogeneous peer effects models and helps clarify the mechanisms behind the effects of ability tracking policies
Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials
Full text link: We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants
- …
