Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy
In conclusion, DD D-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN. (Source: Neurotherapeutics)
Source: Neurotherapeutics - July 26, 2021 Category: Neurology Source Type: research

Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy
SummaryAlthough doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by...
Source: Neurotherapeutics - July 26, 2021 Category: Neurology Source Type: research

REM Sleep Deprivation Impairs Learning and Memory by Decreasing Brain O-GlcNAc Cycling in Mouse
AbstractRapid eye movement (REM) sleep is implicated learning and memory (L/M) functions and hippocampal long-term potentiation (LTP). Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory in mouse is linked to a reduction in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD,O-GlcNAcylation, andO-GlcNAc transferase (OGT) were downregulated whileO-GlcNAcase was upregulated compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), whi...
Source: Neurotherapeutics - July 26, 2021 Category: Neurology Source Type: research

Correction to: Nutritional Ketosis in Parkinson ’s Disease — a Review of Remaining Questions and Insights
(Source: Neurotherapeutics)
Source: Neurotherapeutics - July 26, 2021 Category: Neurology Source Type: research

Histone Mark Profiling in Pediatric Astrocytomas Reveals Prognostic Significance of H3K9 Trimethylation and Histone Methyltransferase SUV39H1
AbstractAlterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics a...
Source: Neurotherapeutics - July 22, 2021 Category: Neurology Source Type: research

Development of EQ-6, a Novel Analogue of Ethoxyquin to Prevent Chemotherapy-Induced Peripheral Neuropathy
AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a common and often dose-limiting side effect of many cancer drugs. Because the onset of neuronal injury is known, it is an ideal clinical target to develop neuroprotective strategies. Several years ago, we had identified ethoxyquin as a potent neuroprotective drug against CIPN through a phenotypic drug screening and demonstrated a novel mechanism of action, inhibition of chaperone domain of heat shock protein 90. To improve its drug-like properties we synthesized a novel analogue of ethoxyquin and named it EQ-6 (6-(5-amino)-ethoxy-2,2,4-trimethyl-1,2-dihydroquino...
Source: Neurotherapeutics - July 21, 2021 Category: Neurology Source Type: research

Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis
In this study, we investigated the therapeutic potential of NLY01 in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our data show that NLY01 delays the onset and attenuates the severity of EAE in a prevention paradigm, when given before disease onset. NLY01 inhibits the activation of immune cells in the spleen and reduces their trafficking into the CNS. In addition, we show that NLY01 suppresses the production of chemokines that are involved in leukocyte recruitment to the site of inflammation. The anti-inflammatory ef fect of NLY01 at the early stage of EAE may block the expression of the genes asso...
Source: Neurotherapeutics - July 14, 2021 Category: Neurology Source Type: research

FRET-Based Screening Identifies p38 MAPK and PKC Inhibition as Targets for Prevention of Seeded α-Synuclein Aggregation
AbstractAggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the traits of the induced pathology, similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic interventions. High-throughput screening of annotated compound libraries could facilitate mechanistic investigation by identifying targ...
Source: Neurotherapeutics - July 13, 2021 Category: Neurology Source Type: research

Myelin Biology
AbstractMyelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system. Myelination not only allows rapid and efficient transmission of electric impulses in the axon by decreasing capacitance and increasing resistance but also influences axonal metabolism and the plasticity of neural circuits. In this review, we will focus on Schwann cells, the glial cells which form myelin in the peripheral nervous system. Here, we will describe the main extrinsic and intrinsic signals inducing Schwann cell differentiation and myelination a...
Source: Neurotherapeutics - July 9, 2021 Category: Neurology Source Type: research

Peripheral Nerve Development and the Pathogenesis of Peripheral Neuropathy: the Sorting Point
AbstractNerve development requires a coordinated sequence of events and steps to be accomplished for the generation of functional peripheral nerves to convey sensory and motor signals. Any abnormality during development may result in pathological structure and function of the nerve, which evolves in peripheral neuropathy. In this review, we will briefly describe different steps of nerve development while we will mostly focus on the molecular mechanisms involved in radial sorting of axons, one of these nerve developmental steps. We will summarize current knowledge of molecular pathways so far reported in radial sorting and ...
Source: Neurotherapeutics - July 9, 2021 Category: Neurology Source Type: research

Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells
AbstractFingolimod is an approved oral treatment for relapsing –remitting multiple sclerosis (RRMS) that modulates agonistically the sphingosin-1-phosphate receptor (S1PR), inhibiting thereby the egress of lymphocytes from the lymph nodes. In this interventional prospective clinical phase IV trial, we longitudinally investigated the impact of fingolimod on fr equencies of NK cell subpopulations by flow cytometry in 17 RRMS patients at baseline and 1, 3, 6, and 12 months after treatment initiation. Clinical outcome was assessed by the Expanded Disability Status Scale (EDSS) and annualized relapse rates (ARR). Ove...
Source: Neurotherapeutics - July 9, 2021 Category: Neurology Source Type: research

Transcutaneous Spinal Neuromodulation Reorganizes Neural Networks in Patients with Cerebral Palsy
This study reports the acute effects of Transcutaneous Electrical Spinal Cord Neuromodulation (SCONE ™, SpineX Inc.) on 12 individuals (ages 2 to 50) diagnosed with cerebral palsy (CP) with Gross Motor Function Classification Scale (GMFCS) levels ranging from I to V. Acute spinal neuromodulation improved the postural and locomotor abilities in 11 out of the 12 patients including the ability to ge nerate bilateral weight bearing stepping in a 2-year-old (GMFCS level IV) who was unable to step. In addition, we observed independent head-control and weight bearing standing with stimulation in a 10-year-old and a 4-year o...
Source: Neurotherapeutics - July 9, 2021 Category: Neurology Source Type: research

Symptomatic Herpes Simplex Virus Infection and Risk of Dementia in US Veterans: a Cohort Study
AbstractA Taiwanese cohort study found that symptomatic herpes simplex virus (HSV) infection was associated with a threefold increased risk of developing dementia; however, antiherpetic medication reduced the risk by 90%. Our aim was to verify and further investigate this finding in the US Veteran population using comprehensive electronic medical records from the Veterans Health Administration (VHA). Eighty-seven thousand six hundred eighty-seven Veterans aged 50 or older with symptomatic HSV-1/HSV-2 infection and 217,895 matched controls were identified in VHA data between January 1, 2001, and December 31, 2014, and follo...
Source: Neurotherapeutics - July 9, 2021 Category: Neurology Source Type: research

Neurokinin Receptor 1 (NK1R) Antagonist Aprepitant Enhances Hematoma Clearance by Regulating Microglial Polarization via PKC/p38MAPK/NF κB Pathway After Experimental Intracerebral Hemorrhage in Mice
The objective of this study was to investigate the role of NK1R and its relation to hematoma clearance after ICH using an autologous blood injection mouse model. A total of 332 adult male CD1 mice were used. We found that the expression levels of NK1R and its endogenous ligand, substance P (SP), were significantly upregulated after ICH. Intraperitoneal administration of the NK1R selective antagonist, Aprepitant, significantly improved neurobehavior, reduced hematoma volume and hemoglobin levels after ICH, and promoted microglia polarization towards M2 phenotype. Aprepitant decreased phosphorylated PKC, p38MAPK, and NF &kap...
Source: Neurotherapeutics - July 9, 2021 Category: Neurology Source Type: research

Gene Editing and Modulation: the Holy Grail for the Genetic Epilepsies?
AbstractEpilepsy is a complex neurological disorder for which there are a large number of monogenic subtypes. Monogenic epilepsies are often severe and disabling, featuring drug-resistant seizures and significant developmental comorbidities. These disorders are potentially amenable to a precision medicine approach, of which genome editing using CRISPR/Cas represents the holy grail. Here we consider mutations in some of the most ‘common’ rare epilepsy genes and discuss the different CRISPR/Cas approaches that could be taken to cure these disorders. We consider scenarios where CRISPR-mediated gene modulation coul...
Source: Neurotherapeutics - July 7, 2021 Category: Neurology Source Type: research

Brain Acetyl-CoA Production and Phosphorylation of Cytoskeletal Proteins Are Targets of CYP46A1 Activity Modulation and Altered Sterol Flux
AbstractCholesterol and 24-hydroxycholesterol are the most abundant brain sterols and represent the substrate and product, respectively, of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. CYP46A1 controls cholesterol elimination and turnover in the brain, the two processes that determine the rate of brain sterol flux through the plasma membranes and thereby the properties of these membranes. Brain sterol flux is decreased inCyp46a1−/− mice compared to wild-type mice and increased in 5XFAD mice (a model of Alzheimer ’s disease) when they are treated with a small dose of efavirenz, a CYP46A1 activato...
Source: Neurotherapeutics - July 7, 2021 Category: Neurology Source Type: research

N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition, but Not Fatty Acid Amide Hydrolase Inhibition, Prevents the Development of Experimental Autoimmune Encephalomyelitis in Mice
This study aims to investigate and compare the effect of NAAA inhibition, FAAH inhibition, and dual inhibition of both enzymes in a mouse model of MS, namely the experimental autoimmune encephalomyelitis (EAE). Our data show that NAAA inhibition strongly decreased the hallmarks of the pathology. Interestingly, FAAH inhibition was less efficient in decreasing inflammatory hallmarks despite the increased NAE levels. Moreover, the inhibition of both NAAA and FAAH, using a dual-inhibitor or the co-administration of NAAA and FAAH inhibitors, did not show an added value compared to NAAA inhibition. Furthermore, our data suggest ...
Source: Neurotherapeutics - July 7, 2021 Category: Neurology Source Type: research

Nutritional Ketosis in Parkinson ’s Disease — a Review of Remaining Questions and Insights
AbstractNutritional ketosis has promise for treating Parkinson ’s disease. Three previous studies explored the use of a ketogenic diet in cohorts with Parkinson’s disease, and, while not conclusive, the data suggest non-motor symptom benefit. Before the ketogenic diet can be considered as a therapeutic option, it is important to establish with greater certa inty that there is a reliable symptomatic benefit: which symptoms or groups of symptoms are impacted (if non-motor symptoms, which ones, and by which mechanism), what timescale is needed to obtain benefit, and how large an effect size can be achieved? To acc...
Source: Neurotherapeutics - July 7, 2021 Category: Neurology Source Type: research

Mesenchymal Stem Cell (MSC) –Derived Extracellular Vesicles Protect from Neonatal Stroke by Interacting with Microglial Cells
Abstract Mesenchymal stem cell (MSC)-based therapies are beneficial in models of perinatal stroke and hypoxia –ischemia. Mounting evidence suggests that in adult injury models, including stroke, MSC-derived small extracellular vesicles (MSC-sEV) contribute to the neuroprotective and regenerative effects of MSCs. Herein, we examined if MSC-sEV protect neonatal brain from stroke and if this effect is mediat ed via communication with microglia. MSC-sEV derived from bone marrow MSCs were characterized by size distribution (NanoSight™) and identity (protein markers). Studies in microglial cells isolated from the i...
Source: Neurotherapeutics - July 7, 2021 Category: Neurology Source Type: research

Association Between Disease-Modifying Therapies Prescribed to Persons with Multiple Sclerosis and Cancer: a WHO Pharmacovigilance Database Analysis
AbstractThe risk of cancer associated with persons with multiple sclerosis (pwMS) prescribed with disease modifying therapies (DMTs) is not well established. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database: VigiBase ®. All consecutive reports of DMTs prescribed to pwMS (alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-β, natalizumab, ocrelizumab, and teriflunomide), and their serious adverse event cases were eligible, excluding those reporting immunosuppressant DMTs used as anticance r ...
Source: Neurotherapeutics - July 6, 2021 Category: Neurology Source Type: research

DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases
AbstractCAG repeat expansion is the genetic cause of nine incurable polyglutamine (polyQ) diseases with neurodegenerative features. Silencing repeat RNA holds great therapeutic value. Here, we developed a repeat-based RNA-cleaving DNAzyme that catalyzes the destruction of expanded CAG repeat RNA of six polyQ diseases with high potency. DNAzyme preferentially cleaved the expanded allele in spinocerebellar ataxia type 1 (SCA1) cells. While cleavage was non-allele-specific for spinocerebellar ataxia type 3 (SCA3) cells, treatment of DNAzyme leads to improved cell viability without affecting mitochondrial metabolism or p62-dep...
Source: Neurotherapeutics - June 23, 2021 Category: Neurology Source Type: research

Specific Blockade of Bone Morphogenetic Protein-2/4 Induces Oligodendrogenesis and Remyelination in Demyelinating Disorders
AbstractOligodendrocyte precursor cells (OPCs) are present in demyelinated lesions of multiple sclerosis (MS) patients. However, their differentiation into functional oligodendrocytes is insufficient, and most lesions evolve into nonfunctional astroglial scars. Blockade of bone morphogenetic protein (BMP) signaling induces differentiation of OPCs into myelin-producing oligodendrocytes. We studied the effect of specific blockade of BMP-2/4 signaling, by intravenous (IV) treatment with anti-BMP-2/4 neutralizing mAb in both the inflammatory model of relapsing experimental autoimmune encephalomyelitis (R-EAE) and the cuprizone...
Source: Neurotherapeutics - June 22, 2021 Category: Neurology Source Type: research

Loss of CC2D1A in Glutamatergic Neurons Results in Autistic-Like Features in Mice
AbstractBiallelic loss-of-function mutations in Coiled-coil and C2 domain containing 1A (CC2D1A) cause autosomal recessive intellectual disability, sometimes comorbid with other neurodevelopmental disabilities, such as autism spectrum disorder (ASD) and seizures. We recently reported that conditional deletion ofCc2d1a in glutamatergic neurons of the postnatal mouse forebrain leads to impaired hippocampal synaptic plasticity and cognitive function. However, the pathogenic origin of the autistic features of CC2D1A deficiency remains elusive. Here, we confirmed that CC2D1A is highly expressed in the cortical zones during embr...
Source: Neurotherapeutics - June 16, 2021 Category: Neurology Source Type: research

In Vivo Wireless Brain Stimulation via Non-invasive and Targeted Delivery of Magnetoelectric Nanoparticles
AbstractWireless and precise stimulation of deep brain structures could have important applications to study intact brain circuits and treat neurological disorders. Herein, we report that magnetoelectric nanoparticles (MENs) can be guided to a targeted brain region to stimulate brain activity with a magnetic field. We demonstrated the nanoparticles ’ capability to reliably evoke fast neuronal responses in cortical slices ex vivo. After fluorescently labeled MENs were intravenously injected and delivered to a targeted brain region by applying a magnetic field gradient, a magnetic field of low intensity (350–450 ...
Source: Neurotherapeutics - June 15, 2021 Category: Neurology Source Type: research

Correction to: The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01061-2 (Source: Neurotherapeutics)
Source: Neurotherapeutics - June 7, 2021 Category: Neurology Source Type: research

Activation of Galanin Receptor 1 with M617 Attenuates Neuronal Apoptosis via ERK/GSK-3 β/TIP60 Pathway After Subarachnoid Hemorrhage in Rats
This study aimed to explore the anti-neuronal apoptosis effect of GalR1 activation after SAH, as well as the underlying mechanisms. GalR1 CRISPR and GalR1 selective agonist, M617, was administered, respectively. Extracellular-signal-regulated kinase (ERK) inhibitor (U0126) and glycogen synthase kinase 3-beta (GSK3- β) CRISPR were administered to investigate the involvement of the ERK/GSK3-β pathway in GalR1-mediated neuroprotection after SAH. Outcome assessments included neurobehavioral tests, western blot, and immunohistochemistry. The results showed that endogenous ligand galanin (Gal) and GalR1 were marke dly ...
Source: Neurotherapeutics - June 4, 2021 Category: Neurology Source Type: research

Correction to: Neuronal Adenylyl Cyclase Targeting Central Plasticity for the Treatment of Chronic Pain
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01065-y (Source: Neurotherapeutics)
Source: Neurotherapeutics - June 4, 2021 Category: Neurology Source Type: research

Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis
AbstractThe continuous adherence to the conventional “one target, one drug” paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study i s aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed networ...
Source: Neurotherapeutics - May 13, 2021 Category: Neurology Source Type: research

α 7 -Acetylcholine Receptor Signaling Reduces Neuroinflammation After Subarachnoid Hemorrhage in Mice
AbstractAneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α7 receptors ( α7-AChR) (receptors shown to have anti-inflammatory effects) would reduce inflammation and improve outcomes. To investigate the level of peripheral inflammation after aSAH, inflammatory markers were measured in plasma samples collected in a cohort of aSAH patients. To study the effect of α7-AChR stimulation, SAH was induced in adult mice which were then treated with a α7-AChR agonist, galanta...
Source: Neurotherapeutics - May 10, 2021 Category: Neurology Source Type: research

Recent Advances in Neuroimaging of Epilepsy
AbstractHuman neuroimaging has had a major impact on the biological understanding of epilepsy and the relationship between pathophysiology, seizure management, and outcomes. This review highlights notable recent advancements in hardware, sequences, methods, analyses, and applications of human neuroimaging techniques utilized to assess epilepsy. These structural, functional, and metabolic assessments include magnetic resonance imaging (MRI), positron emission tomography (PET), and magnetoencephalography (MEG). Advancements that highlight non-invasive neuroimaging techniques used to study the whole brain are emphasized due t...
Source: Neurotherapeutics - May 3, 2021 Category: Neurology Source Type: research

Correction to: Sleep Disturbances Associated with  Neurological Autoimmunity
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01058-x (Source: Neurotherapeutics)
Source: Neurotherapeutics - May 3, 2021 Category: Neurology Source Type: research

Correction to: Sleep Neurology ’s Toolkit at the Crossroads: Challenges and Opportunities in Neurotherapeutics Lost and Found in Translation
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01059-w (Source: Neurotherapeutics)
Source: Neurotherapeutics - April 30, 2021 Category: Neurology Source Type: research

Correction to: CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01062-1 (Source: Neurotherapeutics)
Source: Neurotherapeutics - April 30, 2021 Category: Neurology Source Type: research

Targeting Neuromyelitis Optica Pathogenesis: Results from Randomized Controlled Trials of Biologics
AbstractAdvances in neuromyelitis optica spectrum disorder pathogenesis have allowed the development of targeted drugs. These treatments act on core elements of the disease, including the pro-inflammatory IL-6 pathway (tocilizumab and satralizumab), B cells (rituximab and inebilizumab), and complement (eculizumab). According to recent phase II –III trials, biologics significantly reduced the risk of relapses in aquaporin-4-seropositive patients, whereas results were less striking in the small cohorts of aquaporin-4-seronegative patients. Most adverse events were mild to moderate, with systemic symptoms (headache, art...
Source: Neurotherapeutics - April 28, 2021 Category: Neurology Source Type: research

Correction to: Selective Immunomodulatory and Neuroprotective Effects of a NOD2 Receptor Agonist on Mouse Models of Multiple Sclerosis
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01035-4 (Source: Neurotherapeutics)
Source: Neurotherapeutics - April 27, 2021 Category: Neurology Source Type: research

Network Substrates of Centromedian Nucleus Deep Brain Stimulation in Generalized Pharmacoresistant Epilepsy
AbstractDeep brain stimulation (DBS), specifically thalamic DBS, has achieved promising results to reduce seizure severity and frequency in pharmacoresistant epilepsies, thereby establishing it for clinical use. The mechanisms of action are, however, still unknown. We evidenced the brain networks directly modulated by centromedian (CM) nucleus-DBS and responsible for clinical outcomes in a cohort of patients uniquely diagnosed with generalized pharmacoresistant epilepsy. Preoperative imaging and long-term (2 –11 years) clinical data from ten generalized pharmacoresistant epilepsy patients (mean age at surgery&nb...
Source: Neurotherapeutics - April 26, 2021 Category: Neurology Source Type: research

Correction to: The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01063-0 (Source: Neurotherapeutics)
Source: Neurotherapeutics - April 26, 2021 Category: Neurology Source Type: research

A practical guide to the pharmacological and behavioral therapy of Narcolepsy  
AbstractNarcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current trea...
Source: Neurotherapeutics - April 22, 2021 Category: Neurology Source Type: research

The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway
AbstractAlthough diverse antipsychotic drugs have been developed for the treatment of schizophrenia, most of their mechanisms of action remain elusive. Regulator of G-protein signaling 4 (RGS4) has been reported to be linked, both genetically and functionally, with schizophrenia and is a physiological substrate of the arginylation branch of the N-degron pathway (Arg/N-degron pathway). Here, we show that the atypical antipsychotic drug clozapine significantly inhibits proteasomal degradation of RGS4 proteins without affecting their transcriptional expression. In addition, the levels of Arg- and Phe-GFP (artificial substrate...
Source: Neurotherapeutics - April 21, 2021 Category: Neurology Source Type: research

Restless Legs Syndrome: Contemporary Diagnosis and Treatment
SummaryRestless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination,...
Source: Neurotherapeutics - April 20, 2021 Category: Neurology Source Type: research

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20 —Yet Progress Continues
AbstractMultiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute infla...
Source: Neurotherapeutics - April 20, 2021 Category: Neurology Source Type: research

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGF β Signaling
AbstractAdult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGF β-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells)in vitro. After we injected cynomolgus non-human primates re...
Source: Neurotherapeutics - April 15, 2021 Category: Neurology Source Type: research

Ethical Considerations in Communicating Alzheimer ’s Disease Neuroimaging Biomarker Test Results to Symptomatic Individuals
This article examines ethical issues associated with the return of AD neuroimaging results to cognitively symptomatic individuals. Following a review of research on patient and study partner reactions to learning the results of biomarker testing for AD, we examine ethical issues that will be of increasing significance as the field transitions to an era wherein disease-modifying treatments for AD become available. We first review the ethical justification for returning AD biomarker results to individuals who desire them. We then address a more novel question: whether, and to what extent, clinicians or clinical researchers s...
Source: Neurotherapeutics - April 15, 2021 Category: Neurology Source Type: research

Neuroimaging Biomarkers of Chronic Traumatic Encephalopathy: Targets for the Academic Memory Disorders Clinic
AbstractChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, such as those from contact sports. The pathognomonic lesion for CTE is the perivascular accumulation of hyper-phosphorylated tau in neurons and other cell process at the depths of sulci. CTE cannot be diagnosed during life at this time, limiting research on risk factors, mechanisms, epidemiology, and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE and differentiate it from other neurological disorders. Neuroimaging is an integral component of the clinica...
Source: Neurotherapeutics - April 13, 2021 Category: Neurology Source Type: research

Reversing Accumulation of Polyglucosan Bodies by Virally Delivered CRISPR/Cas9 Genome Editing
(Source: Neurotherapeutics)
Source: Neurotherapeutics - April 13, 2021 Category: Neurology Source Type: research

Correction to: Sleep and Epilepsy: a Focused Review of Pathophysiology, Clinical Syndromes, Co-morbidities, and Therapy
A correction to this paper has been published: https://doi.org/10.1007/s13311-021-01060-3 (Source: Neurotherapeutics)
Source: Neurotherapeutics - April 13, 2021 Category: Neurology Source Type: research

Citicoline Modulates Glaucomatous Neurodegeneration Through Intraocular Pressure-Independent Control
This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural...
Source: Neurotherapeutics - April 13, 2021 Category: Neurology Source Type: research

Exit Strategies in Natalizumab-Treated RRMS at High Risk of Progressive Multifocal Leukoencephalopathy: a Multicentre Comparison Study
Abstract  The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing –remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonanc...
Source: Neurotherapeutics - April 12, 2021 Category: Neurology Source Type: research

Repetitive Transcranial Magnetic Stimulation as a Therapeutic and Probe in Schizophrenia: Examining the Role of Neuroimaging and Future Directions
SummarySchizophrenia is a complex condition associated with perceptual disturbances, decreased motivation and affect, and disrupted cognition. Individuals living with schizophrenia may experience myriad poor outcomes, including impairment in independent living and function as well as decreased life expectancy. Though existing treatments may offer benefit, many individuals still experience treatment resistant and disabling symptoms. In light of the negative outcomes associated with schizophrenia and the limitations in currently available treatments, there is a significant need for novel therapeutic interventions. Repetitive...
Source: Neurotherapeutics - April 12, 2021 Category: Neurology Source Type: research

The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders
AbstractImaging biomarkers play a wide-ranging role in clinical trials for neurological disorders. This includes selecting the appropriate trial participants, establishing target engagement and mechanism-related pharmacodynamic effect, monitoring safety, and providing evidence of disease modification. In the early stages of clinical drug development, evidence of target engagement and/or downstream pharmacodynamic effect —especially with a clear relationship to dose—can provide confidence that the therapeutic candidate should be advanced to larger and more expensive trials, and can inform the selection of the do...
Source: Neurotherapeutics - April 12, 2021 Category: Neurology Source Type: research