HMGB1 Is a Therapeutic Target and Biomarker in Diazepam-Refractory Status Epilepticus with Wide Time Window
AbstractStatus epilepticus (SE), a life-threatening neurologic emergency, is often poorly controlled by the current pharmacological therapeutics, which are limited to a narrow time window. Here, we investigated the proinflammatory cytokine high mobility group box-1 (HMGB1) as a candidate therapeutic target for diazepam (DZP)-refractory SE. We found that HMGB1 was upregulated and translocated rapidly during refractory SE period. Exogenous HMGB1 was sufficient to directly induce DZP-refractory SE in nonrefractory SE. Neutralization of HMGB1 with an anti-HMGB1 monoclonal antibody decreased the incidence of SE and alleviated t...
Source: Neurotherapeutics - December 4, 2019 Category: Neurology Source Type: research

Brain –Machine Interface Induced Morpho-Functional Remodeling of the Neural Motor System in Severe Chronic Stroke
In this study, we investigated neural plasticity in the moto r network of severely impaired chronic stroke patients after an EEG-BMI-based treatment reinforcing sensorimotor contingency of ipsilesional motor commands. Our structural connectivity analysis revealed decreased fractional anisotropy in the splenium and body of the corpus callosum, and in the contr alesional hemisphere in the posterior limb of the internal capsule, the posterior thalamic radiation, and the superior corona radiata. Functional connectivity analysis showed decreased negative interhemispheric coupling between contralesional and ipsilesional sensorim...
Source: Neurotherapeutics - December 4, 2019 Category: Neurology Source Type: research

Benzodiazepines, z-Hypnotics, and Risk of Dementia: Special Considerations of Half-Lives and Concomitant Use
AbstractThe utilization of benzodiazepines (BZDs) and z-hypnotics has substantially increased with the aging of the population, but the risk of BZDs and z-hypnotics in the development of dementia remains a strong concern. This cohort study aimed to evaluate the risk of BZDs and z-hypnotics for subsequent dementia development with a special consideration of their half-lives and the concomitant use of these medications. People aged 65 years and older who were newly prescribed oral BZDs or z-hypnotics between 2003 and 2012 were identified from Taiwan ’s National Health Insurance Research Database. All BZDs were categori...
Source: Neurotherapeutics - December 4, 2019 Category: Neurology Source Type: research

Modeling Polyglutamine Expansion Diseases with Induced Pluripotent Stem Cells
AbstractPolyglutamine expansion disorders, which include Huntington ’s disease, have expanded CAG repeats that result in polyglutamine expansions in affected proteins. How this specific feature leads to distinct neuropathies in 11 different diseases is a fascinating area of investigation. Most proteins affected by polyglutamine expansions are ubiquitously expresse d, yet their mechanisms of selective neurotoxicity are unknown. Induced pluripotent stem cells have emerged as a valuable tool to model diseases, understand molecular mechanisms, and generate relevant human neural and glia subtypes, cocultures, and organoid...
Source: Neurotherapeutics - December 2, 2019 Category: Neurology Source Type: research

Fabrication and Evaluation of a Xenogeneic Decellularized Nerve-Derived Material: Preclinical Studies of a New Strategy for Nerve Repair
In conclusion, the novel nerve repair membrane derived from xenogeneic decellularized nerves described in this study shows great potential auxiliary clinical treatment for peripheral nerve injuries. (Source: Neurotherapeutics)
Source: Neurotherapeutics - November 22, 2019 Category: Neurology Source Type: research

Gender-Specific Beneficial Effects of Docosahexaenoic Acid Dietary Supplementation in G93A-SOD1 Amyotrophic Lateral Sclerosis Mice
AbstractDocosahexaenoic acid (DHA) is an essential fatty acid modulating key nervous system functions, including neuroinflammation, and regulation of pre- and postsynaptic membrane formation. DHA concentration decreases in the lumbar spinal cord (LSC) of amyotrophic lateral sclerosis (ALS) patients and murine preclinical models. Using a dietary supplementation, we increased DHA levels (2% mean increase,p 
Source: Neurotherapeutics - November 21, 2019 Category: Neurology Source Type: research

Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31)
AbstractSpinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n in an intron of the gene calledBEAN1 (brain expressed, associated with Nedd4). By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA)n was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA)...
Source: Neurotherapeutics - November 21, 2019 Category: Neurology Source Type: research

Picrorhiza kurroa Prevents Memory Deficits by Inhibiting NLRP3 Inflammasome Activation and BACE1 Expression in 5xFAD Mice
This study aims to report the significance of PK treatment in markedly improving spatial learning memory and dramatically decreasing A β levels in Tg6799 mice, also known 5xFAD mice, which have five familial AD (FAD) mutations. Remarkably, these effects correlated with reversal of disease-related microglial neuroinflammation, as evidenced by shifting microglia phenotypes from the inflammatory form to the anti-inflammatory form and inhibiting the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 inflammasome activity. Moreover, PK administration induced silent information reg...
Source: Neurotherapeutics - November 18, 2019 Category: Neurology Source Type: research

Vildagliptin Attenuates Huntington ’s Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model
In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model. (Source: Neurotherapeutics)
Source: Neurotherapeutics - November 14, 2019 Category: Neurology Source Type: research

Diagnosis and Management of Alcohol Use Disorder in Patients with Liver Disease: Lights and Shadows
AbstractAlcohol use disorder is the most common cause of advanced liver disease in the Western world. Diagnosis of alcohol use disorder can be difficult because patients with liver disease tend to deny alcohol intake for the fear of being excluded from treatment and because available biomarkers of alcohol intake have poor specificity in these patients. Alcohol abstinence is the cornerstone of the therapy in these patients. However, pharmacological treatments for alcohol use disorders have not been formally tested in patients with advanced liver disease, except for baclofen. Psychosocial intervention became crucial in these...
Source: Neurotherapeutics - November 11, 2019 Category: Neurology Source Type: research

Long Noncoding RNA HOTAIRM1 Maintains Tumorigenicity of Glioblastoma Stem-Like Cells Through Regulation of HOX Gene Expression
In this study, GSCs were established by neurosphere cultures of primary glioblastoma cells and validated by the expression of GSC marker CD133. The expression of the long noncoding RNA HOTAIRM1 was detected using real-time quantitative reverse transcription PCR (qRT-PCR). The role of HOTAIRM1 in the proliferation, apoptosis, stemness, and tumorigenicity of GSCs was investigated by soft agar colony formation, flow cytometry, TUNEL analysis, sphere formation, andin vivo xenograft models through silencing of HOTAIRM1. The expression of HOTAIRM1 and the neighboring HOX genes were analyzed by qRT-PCR in different grades of glio...
Source: Neurotherapeutics - November 5, 2019 Category: Neurology Source Type: research

From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation
AbstractSpinocerebellar ataxia type 3 (SCA3), also known as Machado –Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in theATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a reali...
Source: Neurotherapeutics - November 5, 2019 Category: Neurology Source Type: research

Molecular Mechanisms and Therapeutics for SBMA/Kennedy ’s Disease
AbstractSpinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caus...
Source: Neurotherapeutics - November 4, 2019 Category: Neurology Source Type: research

Anti-Neuronal Antibodies Within the IVIg Preparations: Importance in Clinical Practice
AbstractOur study objective was testing for anti-neuronal autoantibodies within commercially available intravenous immunoglobulin (IVIg) preparations. Sixteen samples from 5 different commercially available IVIg preparations were tested with cell-based assays (CBA) and enzyme-linked immunosorbent assay (ELISA) to detect and characterize common neuronal autoantibodies, and with immunohistochemistry on teased fibers from mouse sciatic nerve and on mouse brain sections to screen for nodal and not yet identified neuronal antigens. In 15/16 IVIg preparations, anti-GAD antibodies were detected in titers ranging from 40 to 1507 I...
Source: Neurotherapeutics - October 31, 2019 Category: Neurology Source Type: research

Pathogenic Mechanisms and Therapy Development for C9orf72 Amyotrophic Lateral Sclerosis/Frontotemporal Dementia
AbstractIn 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of ...
Source: Neurotherapeutics - October 30, 2019 Category: Neurology Source Type: research

Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer ’s Mouse Model
AbstractPreviously, we reported that the neurosteroid allopregnanolone (Allo) promoted neural stem cell regeneration, restored cognitive function, and reduced Alzheimer ’s Disease (AD) pathology in the triple transgenic Alzheimer’s mouse model (3xTgAD). To investigate the underlying systems biology of Allo action in AD modelsin vivo, we assessed the regulation of Allo on the bioenergetic system of the brain. Outcomes of these analysis indicated that Allo significantly reversed deficits in mitochondrial respiration and biogenesis and key mitochondrial enzyme activity and reduced lipid peroxidation in the 3xTgAD ...
Source: Neurotherapeutics - October 29, 2019 Category: Neurology Source Type: research

Opioid Craving in Human Laboratory Settings: a Review of the Challenges and Limitations
AbstractThere are many factors that need to be taken into consideration when measuring craving in a human laboratory study. This review summarizes and discusses some of the major challenges researchers are faced with when assessing opioid craving in clinical research. First, there are wide range of available assessments that have been developed for measuring craving and depending on the research questions or the underlying constructs targeted, some may be more appropriate than others. In addition to establishing the methodological point of departure for designing a study with craving, there are also different participant c...
Source: Neurotherapeutics - October 24, 2019 Category: Neurology Source Type: research

Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease
In this study, the effect on retinal function and morphology of clinically safe doses of orally delivered tonabersat, a small molecule connexin hemichannel blocker, was investigated in the light-damaged retina animal model of dry AMD and in a spontaneous rat model of DR. Clinical parameters (fundus imaging, optical coherence tomography (OCT), and electroretinography) and inflammatory markers (immunohistochemistry for Iba-1 microglial marker, astrocyte marker glial fibrillary acidic protein, and Connexin43 protein expression) were assessed. Tonabersat treatment reduced inflammation in the retina in parallel with preservatio...
Source: Neurotherapeutics - October 21, 2019 Category: Neurology Source Type: research

Levo-corydalmine Attenuates Vincristine-Induced Neuropathic Pain in Mice by Upregulating the Nrf2/HO-1/CO Pathway to Inhibit Connexin 43 Expression
In this study, we investigated a role for Nrf2/HO-1/CO in mediating vincristine-induced neuroinflammation by inhibiting connexin 43 (Cx43) production in the spinal cord following the intrathecal application of the HO-1 inducer protoporphyrin IX cobalt chloride (CoPP) or inhibitor protoporphyrin IX zinc (ZnPP), and we analyzed the underlying mechanisms by which levo-corydalmine (l-CDL, a tetrahydroprotoberberine) attenuates vincristine-induced pain. Treatment with levo-corydalmine or oxycodone hydrochloride (a semisynthetic opioid analgesic, used as a positive control) attenuated vincristine-induced persistent pain hypersen...
Source: Neurotherapeutics - October 15, 2019 Category: Neurology Source Type: research

Receptor Tyrosine Kinases as Therapeutic Targets for Alcohol Use Disorder
AbstractThe receptor tyrosine kinases (RTKs) are a large family of proteins that transduce extracellular signals to the inside of the cell to ultimately affect important cellular functions such as cell proliferation, survival, apoptosis, differentiation, and migration. They are expressed in the nervous system and can regulate behavior through modulation of neuronal and glial function. As a result, RTKs are implicated in neurodegenerative and psychiatric disorders such as depression and addiction. Evidence has emerged that 5 RTKs (tropomyosin-related kinase B (TrkB), RET proto-oncogene (RET), anaplastic lymphoma kinase (ALK...
Source: Neurotherapeutics - October 15, 2019 Category: Neurology Source Type: research

Abstracts from HSG 2019
(Source: Neurotherapeutics)
Source: Neurotherapeutics - October 8, 2019 Category: Neurology Source Type: research

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington ’s Disease: Insights from In Vitro and In Vivo Models
AbstractHuntington ’s disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in thehuntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the co...
Source: Neurotherapeutics - September 16, 2019 Category: Neurology Source Type: research

Early and Sustained Increases in Leukotriene B 4 Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients
We examined the prognostic significance of LTB4 levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB4 levels were found to increase rapidly, roughly doubling within 24  h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB4 rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral ...
Source: Neurotherapeutics - September 13, 2019 Category: Neurology Source Type: research

Brain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington ’s Disease
AbstractThere is currently no disease-modifying treatment for Huntington ’s disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc defici ency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze,...
Source: Neurotherapeutics - September 13, 2019 Category: Neurology Source Type: research

Letter from the Editor-in-Chief: Growth of the Journal
(Source: Neurotherapeutics)
Source: Neurotherapeutics - September 13, 2019 Category: Neurology Source Type: research

The Medical Management of Cerebral Edema: Past, Present, and Future Therapies
AbstractCerebral edema is commonly associated with cerebral pathology, and the clinical manifestation is largely related to the underlying lesioned tissue. Brain edema usually amplifies the dysfunction of the lesioned tissue and the burden of cerebral edema correlates with increased morbidity and mortality across diseases. Our modern-day approach to the medical management of cerebral edema has largely revolved around, an increasingly artificial distinction between cytotoxic and vasogenic cerebral edema. These nontargeted interventions such as hyperosmolar agents and sedation have been the mainstay in clinical practice and ...
Source: Neurotherapeutics - September 11, 2019 Category: Neurology Source Type: research

N -Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug
AbstractIn our recent studies, we identified compoundN-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in th...
Source: Neurotherapeutics - September 4, 2019 Category: Neurology Source Type: research

Activation of Melanocortin 1 Receptor Attenuates Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage viathe Suppression of Neuroinflammation through AMPK/TBK1/NF- κB Pathway in Rats
AbstractNeuroinflammation plays a vital role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The hypothesis of this study was that activation of melanocortin 1 receptor (MC1R) with BMS-470539 attenuates EBI by suppression of neuroinflammation after SAH. We utilized BMS-470539, MSG-606, and MRT-68601 to verify the neuroprotective effects of MC1R. We evaluated brain water content, short-term and long-term neurobehavior after SAH. Western blotting and immunofluorescence staining were utilized to assess the changes of protein levels. The results of western blotting suggested that the expressions of MC1R, p...
Source: Neurotherapeutics - August 29, 2019 Category: Neurology Source Type: research

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?
AbstractMultiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG3...
Source: Neurotherapeutics - August 28, 2019 Category: Neurology Source Type: research

Effects of Natalizumab and Fingolimod on Clinical, Cognitive, and Magnetic Resonance Imaging Measures in Multiple Sclerosis
AbstractStudies comparing the effects of natalizumab and fingolimod in relapsing –remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white matter (WM), and deep GM were measured. Fifteen healthy controls (HC) were also scan...
Source: Neurotherapeutics - August 26, 2019 Category: Neurology Source Type: research

Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?
The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2  years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses:
Source: Neurotherapeutics - August 26, 2019 Category: Neurology Source Type: research

Non-invasive Brain Stimulation for Alcohol Use Disorders: State of the Art and Future Directions
AbstractAlcohol use disorders remain one of the leading causes of mortality and morbidity across the world, yet despite this impact, there are few treatment options for patients suffering from these disorders. To this end, non-invasive brain stimulation, most commonly utilizing technologies including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), has recently emerged as promising potential treatments for alcohol use disorders. Enthusiasm for these interventions is fueled by their non-invasive nature, generally favorable safety profile, and ability to target and modulate brain re...
Source: Neurotherapeutics - August 26, 2019 Category: Neurology Source Type: research

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2
AbstractThe effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment. A better understanding of the uncovered molecular mechanisms of the disease allowed the scient...
Source: Neurotherapeutics - August 21, 2019 Category: Neurology Source Type: research

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7
AbstractSpinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in un...
Source: Neurotherapeutics - August 20, 2019 Category: Neurology Source Type: research

Computer-Assisted Planning for Stereoelectroencephalography (SEEG)
We report a prospective validation study of the use of EpiNav (UCL, London, UK)  as a clinical decision support software for SEEG. Thirteen consecutive patients (125 electrodes) undergoing SEEG were prospectively recruited. EpiNav was used to generate 3D models of critical structures (including vasculature) and other important regions of interest. Manual planning utilizing the same 3D models was performed in advance of CAP. CAP was subsequently employed to automatically generate a plan for each patient. The treating neurosurgeon was able to modify CAP generated plans based on their preference. The plan with the lowest...
Source: Neurotherapeutics - August 20, 2019 Category: Neurology Source Type: research

Cyclooxygenase-2 Induced the β-Amyloid Protein Deposition and Neuronal Apoptosis Via Upregulating the Synthesis of Prostaglandin E 2 and 15-Deoxy-Δ 12,14 -prostaglandin J 2
AbstractElevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) have been shown to be involved in the pathogenesis of Alzheimer ’s disease. Analysis of the underlying mechanisms elucidated a function of sequential PGE2 and PGD2 synthesis in regulating β-amyloid protein (Aβ) deposition by modulating tumor necrosis factor α (TNF-α)-dependent presenilin (PS)1/2 activity in COX-2 and APP/PS1 crossed mice. Specifically, COX-2 overexpression accelerates the expression of microsomal PGE synthase-1 (mPGES-1) and lipocalin-type prostaglandin D synthas e (L-PGDS), leading to the synthesis of ...
Source: Neurotherapeutics - August 7, 2019 Category: Neurology Source Type: research

Neuroprotective and Antioxidant Effect of Ginkgo biloba Extract Against AD and Other Neurological Disorders
AbstractAlzheimer ’s disease (AD) is the most common progressive human neurodegenerative disorder affecting elderly population worldwide. Hence, prevention of AD has been a priority of AD research worldwide. Based on understanding of disease mechanism, different therapeutic strategies involving synthetic and herbal approaches are being used against AD. Among the herbal extract,Ginkgo biloba extract (GBE) is one of the most investigated herbal remedy for cognitive disorders and Alzheimer ’s disease (AD). Standardized extract ofGinkgo biloba is a popular dietary supplement taken by the elderly population to impro...
Source: Neurotherapeutics - August 2, 2019 Category: Neurology Source Type: research

Sleep as a Therapeutic Target in the Aging Brain
AbstractSleep is a behavioral phenomenon conserved among mammals and some invertebrates, yet the biological functions of sleep are still being elucidated. In humans, sleep time becomes shorter, more fragmented, and of poorer quality with advancing age. Epidemiologically, the development of age-related neurodegenerative diseases such as Alzheimer ’s and Parkinson’s disease is associated with pronounced sleep disruption, whereas emerging mechanistic studies suggest that sleep disruption may be causally linked to neurodegenerative pathology, suggesting that sleep may represent a key therapeutic target in the preve...
Source: Neurotherapeutics - August 2, 2019 Category: Neurology Source Type: research

Peripheral Administration of IL-13 Induces Anti-inflammatory Microglial/Macrophage Responses and Provides Neuroprotection in Ischemic Stroke
AbstractNeuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 imm...
Source: Neurotherapeutics - August 1, 2019 Category: Neurology Source Type: research

DNA Damage Repair in Huntington ’s Disease and Other Neurodegenerative Diseases
AbstractRecent genome-wide association studies of Huntington ’s disease (HD) primarily highlighted genes involved in DNA damage repair mechanisms as modifiers of age at onset and disease severity, consistent with evidence that more DNA repair genes are being implicated in late age–onset neurodegenerative diseases. This provides an exciting opportunity to advance therapeutic development in HD, as these pathways have already been under intense investigation in cancer research. Also emerging are the roles of other polyglutamine disease proteins in DNA damage repair mechanisms. A potential universal trigger of oxid...
Source: Neurotherapeutics - July 30, 2019 Category: Neurology Source Type: research

The Role of Estrogen in Brain and Cognitive Aging
AbstractThere are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer ’s disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show i...
Source: Neurotherapeutics - July 30, 2019 Category: Neurology Source Type: research

The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis
AbstractAmyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model. To circumscribe these issues, we screened 3,765 novel small molecule derivatives of pimozide, a recently ident...
Source: Neurotherapeutics - July 24, 2019 Category: Neurology Source Type: research

Correction to: Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration
This article was corrected to include a revised version of figure 2 overlooked by the Publisher during the production process. (Source: Neurotherapeutics)
Source: Neurotherapeutics - July 24, 2019 Category: Neurology Source Type: research

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice
AbstractNeuropeptide Y (NPY) has been demonstrated to exert stress buffering effects and promote resilience. Non-invasive intranasal (IN) application of NPY to rodents is able to mitigate traumatic stress-induced behavioral changes as well as dysfunction of the hypothalamic-pituitary-adrenal (HPA)  axis. However, it is unknown whether IN NPY could prevent the behavioral, pro-inflammatory and neurochemical responses to peripheral immune activation by the Toll-like receptor 4 (TLR4) stimulant lipopolysaccharide (LPS). Therefore, we analyzed the effects of IN NPY (100 μg) on the behavioral si ckness response (red...
Source: Neurotherapeutics - July 23, 2019 Category: Neurology Source Type: research

Moving Towards Therapy in SCA1: Insights from Molecular Mechanisms, Identification of Novel Targets, and Planning for Human Trials
AbstractThe spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders inherited in an autosomal dominant fashion. The SCAs result in progressive gait imbalance, incoordination of the limbs, speech changes, and oculomotor dysfunction, among other symptoms. Over the past few decades, significant strides have been made in understanding the pathogenic mechanisms underlying these diseases. Although multiple efforts using a combination of genetics and pharmacology with small molecules have been made towards developing new therapeutics, no FDA approved treatment currently exists. In this review, we focus on SCA1, ...
Source: Neurotherapeutics - July 23, 2019 Category: Neurology Source Type: research

Molecular Mechanisms and Therapeutics for SCA17
AbstractSpinocerebellar ataxia type 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP), which functions as a general transcription factor. Like other polyQ expansion-mediated diseases, SCA17 is characterized by late-onset and selective neurodegeneration, despite the disease protein being ubiquitously expressed in the body. To date, the pathogenesis of polyQ diseases is not fully understood, and there are no effective treatments for these devastating disorders. The well-characterized function of TBP and typical neurodegeneration in SCA17 give us opportunities to understand how poly...
Source: Neurotherapeutics - July 17, 2019 Category: Neurology Source Type: research

Molecular Mechanisms and Therapeutics for the GAA ·TTC Expansion Disease Friedreich Ataxia
AbstractFriedreich ataxia (FRDA), the most common inherited ataxia, is caused by transcriptional silencing of the nuclearFXN gene, encoding the essential mitochondrial protein frataxin. Currently, there is no approved therapy for this fatal disorder. Gene silencing in FRDA is due to hyperexpansion of the triplet repeat sequence GAA ·TTC in the first intron of theFXN gene, which results in chromatin histone modifications consistent with heterochromatin formation. Frataxin is involved in mitochondrial iron homeostasis and the assembly and transfer of iron-sulfur clusters to various mitochondrial enzymes and components...
Source: Neurotherapeutics - July 17, 2019 Category: Neurology Source Type: research

Tetramethylpyrazine Analogue T-006 Promotes the Clearance of Alpha-synuclein by Enhancing Proteasome Activity in Parkinson ’s Disease Models
AbstractParkinson ’s disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized in part by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The main pathological hallmark of PD is the intraneuronal accumulation of misfolded α-synuclein (α- syn) aggregates. Mutations in the SNCA gene (encoding α-syn) and variations in its copy number are associated with some forms of familial PD. In the present study, T-006, a new tetramethylpyrazine (TMP) derivative with recently reported anti-Alzheimer activity, is shown to significantly pro...
Source: Neurotherapeutics - July 16, 2019 Category: Neurology Source Type: research

Neurotherapeutics of the Aging Brain: Complexity Meets Complexity
(Source: Neurotherapeutics)
Source: Neurotherapeutics - July 9, 2019 Category: Neurology Source Type: research

Correction to: Transcranial Magneto-Acoustic Stimulation Improves Neuroplasticity in Hippocampus of Parkinson ’s Disease Model Mice
The authors would like to correct X. Zhou ’s grant number from the National Natural Science Foundation of China to 81601633. (Source: Neurotherapeutics)
Source: Neurotherapeutics - July 9, 2019 Category: Neurology Source Type: research