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Ochsner Journal 2021Fibromyalgia, a complex disorder that affects 1% to 5% of the population, presents as widespread chronic musculoskeletal pain without physical or laboratory signs of... (Review)
Review
Fibromyalgia, a complex disorder that affects 1% to 5% of the population, presents as widespread chronic musculoskeletal pain without physical or laboratory signs of any specific pathologic process. The mechanism, while still being explored, suggests central sensitization and disordered pain regulation at the spinal cord and supraspinal levels, with a resulting imbalance between excitation and inhibition that may alter central nervous system nociceptive processing. Nociceptive hypersensitivity results from activity of the N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic synaptic transmission in the spinal cord and brain. Because ketamine, an NMDAR antagonist, may reduce induction of synaptic plasticity and maintenance of chronic pain states, the study of its use in intravenous form to treat fibromyalgia has increased. We conducted a literature search with the objectives of examining the effect of intravenous ketamine administration on pain relief, identifying side effects, and highlighting the need for clinical studies to evaluate ketamine infusion treatment protocols for patients with fibromyalgia. We used the keywords "fibromyalgia," "chronic pain," "ketamine," "intravenous," and "infusion" and found 7 publications that included 118 patients with fibromyalgia who met inclusion criteria. Clinical studies revealed a short-term reduction-only for a few hours after the infusions-in self-reported pain intensity with single, low-dose, intravenous ketamine infusions, likely attributable to nociception-dependent central sensitization in fibromyalgia via NMDAR blockade. Case studies suggest that increases in the total dose of ketamine and longer, more frequent infusions may be associated with more effective pain relief and longer-lasting analgesia. Another neurotransmitter release may be contributing to this outcome. This systematic review suggests a dose response, indicating potential efficacy of intravenous ketamine in the treatment of fibromyalgia.
PubMed: 34984054
DOI: 10.31486/toj.21.0038 -
Frontiers in Immunology 2021Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Combined Modality Therapy; Complement Inactivating Agents; Complement System Proteins; Disease Management; Disease Susceptibility; Drug Development; Humans; Myasthenia Gravis; Treatment Outcome
PubMed: 34456922
DOI: 10.3389/fimmu.2021.715036 -
Frontiers in Neural Circuits 2021The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex...
The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex connections with the other basal ganglia nuclei and brain regions. Recently, with the adoption of sophisticated genetic tools, substantial advances have been made in understanding the distinct molecular, anatomical, electrophysiological, and functional properties of GPe neurons and non-neuronal cells. Impairments in dopamine transmission in the basal ganglia contribute to Parkinson's disease (PD), the most common movement disorder that severely affects the patients' life quality. Altered GPe neuron activity and synaptic connections have also been found in both PD patients and pre-clinical models. In this review, we will summarize the main findings on the composition, connectivity and functionality of different GPe cell populations and the potential GPe-related mechanisms of PD symptoms to better understand the cell type and circuit-specific roles of GPe in both normal and PD conditions.
Topics: Basal Ganglia; Dopamine; Globus Pallidus; Humans; Neurons; Parkinson Disease
PubMed: 33737869
DOI: 10.3389/fncir.2021.645287 -
Frontiers in Aging Neuroscience 2020Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in...
Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in patients. The endplate, the post-synaptic part of the neuromuscular junction (NMJ), occupies 0.1% of the myofiber surface area only, but is composed of millions of acetylcholine receptors (AChRs) that are efficient in binding to acetylcholine (ACh) and triggering skeletal muscle contraction. This systematic review aims to examine aging-associated alterations of post-synaptic AChRs, including morphology, function and related gene expression. A systematic literature search was conducted in PubMed, Embase and Web of Science with relevant keywords by two independent reviewers. Original pre-clinical and clinical studies regarding AChRs changes during aging with available full text and written in English were included. Information was extracted from the included studies for further review. In total, 30 articles were included. Various parameters assessing AChRs alterations by radioassay, immunofluorescence, electrophysiology and mechanical test were reported. Endplate fragmentation and denervation were common in old skeletal muscles during aging. To ensure efficient NMJ transmission and force generation, type I or IIb muscle fibers tended to have increased ACh quanta releasing after electrical stimulations, while type IIa muscle fibers tended to have stronger binding between ACh and AChRs, but the overall function of AChRs was reduced during aging. Alterations of AChRs area depended on muscle type, species and the progress of muscle atrophy and type I muscles fibers tended to demonstrate enlarging AChRs areas. Myogenic regulator factors (MRFs) can regulate the expression of AChRs subunits, while decreased MRF4 may lead to expression changes of AChRs subunits during aging. Sarcoglycan-α can delay low-density lipoprotein receptor-related protein 4 (LRP4) degradation. This protein was increased in old muscles but still cannot suppress the degradation of LRP4. Investigating the role of these AChRs-related genes in the process of aging may provide a potential target to treat sarcopenia.
PubMed: 33362532
DOI: 10.3389/fnagi.2020.597811 -
Journal of Integrative Neuroscience Jun 2020Active compounds and corresponding targets of the traditional Chinese herb, were obtained from systems pharmacological database and placed into ClueGO for gene ontology...
Active compounds and corresponding targets of the traditional Chinese herb, were obtained from systems pharmacological database and placed into ClueGO for gene ontology analysis. The targets of depression were obtained from the Online Mendelian Inheritance in Man, the Therapeutic Target Database, and the Pharmacogenomics Knowledge Base. Compound-target and target-pathway networks were constructed using Cytoscape, and then their topological parameters were analyzed. The targets of and depression were mapped to pathways, thereby constructing antidepressant pathways of . It was found that has 82 different active compounds and 306 relevant potential targets. Also, 107 unrepeatable targets related to depression were found. In all, 26 common targets were found to be the direct anti-depression targets of and 9 pathways of related to depression were divided into three modules (synaptic transmission, cell apoptosis, and immune-inflammatory). The formula was found to have synergistic antidepressant effects due to aspects of its herb composition and the active compounds therein, giving rise to potential targets and signaling pathways related to depression. Its antidepressant mechanisms were found to mainly involve the regulation of synaptic transmission, cell apoptosis, and immune-mediated inflammation.
Topics: Antidepressive Agents; Drugs, Chinese Herbal; Gene Ontology; Humans; Pharmacogenetics; Phytotherapy
PubMed: 32706203
DOI: 10.31083/j.jin.2020.02.1246 -
Neuroscience and Biobehavioral Reviews Nov 2020The aim of this systematic review was to provide insight in inhibitory control (prepotent response inhibition and interference control) in trauma-exposed youth from a... (Review)
Review
The aim of this systematic review was to provide insight in inhibitory control (prepotent response inhibition and interference control) in trauma-exposed youth from a developmental perspective and exploring the effects of prolonged stress. A systematic search was conducted, resulting in 1722 abstracts. Of those, 33 studies met inclusion criteria. Twelve studies measured prepotent response inhibition (Go/no-go and Stop-signal task), 20 studies measured interference control (Flanker and Stroop task), and one measured both. Some studies indeed found evidence for prolonged trauma exposure impeding both subcomponents of inhibitory control, although others did not. At a later age, inhibitory control problems on task performance seem to disappear. However, distinct patterns of brain activity may suggest that those individuals employ compensation strategies. Together, the findings may suggest that non-specific inhibitory control problems occur after prolonged trauma exposure, with older youth possibly employing compensation strategies on the tasks. Future studies may provide a clearer picture of the compensation strategies and the circumstances in which they become visible.
Topics: Adolescent; Humans; Inhibition, Psychological; Psychomotor Performance; Reaction Time; Synaptic Transmission; Task Performance and Analysis
PubMed: 32574571
DOI: 10.1016/j.neubiorev.2020.06.001 -
Clinical Neurology and Neurosurgery Jul 2020Increasing research reports neurological manifestations of COVID-19 patients. SARS-CoV-2 shares homology with other human coronaviruses that have also had nervous system...
BACKGROUND
Increasing research reports neurological manifestations of COVID-19 patients. SARS-CoV-2 shares homology with other human coronaviruses that have also had nervous system involvement.
OBJECTIVE
To review the neurological aspects of SARS-cov2 and other coronavirus, including transmission pathways, mechanisms of invasion into the nervous system, and mechanisms of neurological disease.
METHODS
We conducted a systematic review of articles in PubMed, SCOPUS and EMBASE data bases. Reviewed evidence is presented in sections of this manuscript which includes pathogenesis, neuro-invasion, encephalitis, Guillain-Barré, ADEM, multiple sclerosis, polyneuropathy, and cerebrovascular disease.
RESULTS
A total 67 studies were included in the final analysis of experimental studies, case reports, series of cases, cohort studies, and systematic reviews related to neurological manifestations of SARS- CoV-2 and other human coronavirus infections. The SARS-CoV-2 receptor is expressed in the nervous system. Common reported symptoms included hyposmia, headaches, weakness, altered consciousness. Encephalitis, demyelination, neuropathy, and stroke have been associated with COVID-19. Infection through the cribriform plate and olfactory bulb and dissemination through trans-synaptic transfer are some of the mechanisms proposed. Invasion of the medullary cardiorespiratory center by SARS-CoV-2 may contribute to the refractory respiratory failure observed in critically-ill COVID-19 patients.
CONCLUSION
An increasing number of reports of COVID-19 patients with neurological disorders add to emergent experimental models with neuro-invasion as a reasonable concern that SARS-CoV-2 is a new neuropathogen. How it may cause acute and chronic neurologic disorders needs to be clarified in future research.
Topics: Betacoronavirus; Brain; COVID-19; Coronavirus Infections; Humans; Nervous System Diseases; Observational Studies as Topic; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 32422545
DOI: 10.1016/j.clineuro.2020.105921 -
Frontiers in Physiology 2020Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and...
Misfolded proteins are the main common feature of neurodegenerative diseases, thereby, normal proteostasis is an important mechanism to regulate the neural survival and the central nervous system functionality. The ubiquitin-proteasome system (UPS) is a non-lysosomal proteolytic pathway involved in numerous normal functions of the nervous system, modulation of neurotransmitter release, synaptic plasticity, and recycling of membrane receptors or degradation of damaged and regulatory intracellular proteins. Aberrant accumulation of intracellular ubiquitin-positive inclusions has been implicated to a variety of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Myeloma (MM). Genetic mutation in deubiquitinating enzyme could disrupt UPS and results in destructive effects on neuron survival. To date, various agents were characterized with proteasome-inhibitory potential. Proteins of the ubiquitin-proteasome system, and in particular, E3 ubiquitin ligases, may be promising molecular targets for neurodegenerative drug discovery. Phytochemicals, specifically polyphenols (PPs), were reported to act as proteasome-inhibitors or may modulate the proteasome activity. PPs modify the UPS by means of accumulation of ubiquitinated proteins, suppression of neuronal apoptosis, reduction of neurotoxicity, and improvement of synaptic plasticity and transmission. This is the first comprehensive review on the effect of PPs on UPS. Here, we review the recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders. This review attempts to summarize the latest reports on the neuroprotective properties involved in the proper functioning of natural polyphenolic compounds with implication for targeting ubiquitin-proteasome pathway in the neurodegenerative diseases. We highlight the evidence suggesting that polyphenolic compounds have a dose and disorder dependent effects in improving neurological dysfunctions, and so their mechanism of action could stimulate the UPS, induce the protein degradation or inhibit UPS and reduce protein degradation. Future studies should focus on molecular mechanisms by which PPs can interfere this complex regulatory system at specific stages of the disease development and progression.
PubMed: 32411012
DOI: 10.3389/fphys.2020.00361 -
Osteoarthritis and Cartilage Jul 2020Quantitative sensory testing (QST) is a psychophysical test used to quantify somatosensory sensation under normal or pathological conditions including osteoarthritis... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Quantitative sensory testing (QST) is a psychophysical test used to quantify somatosensory sensation under normal or pathological conditions including osteoarthritis (OA).
OBJECTIVE
This study aimed to conduct a systematic review and meta-analysis of studies using QST in healthy and osteoarthritic cats, registered at Systematic Review Research Facility (#26-06-2017).
DESIGN
Hierarchical models with random intercepts for each individual study extracted through the systematic review were fit to subject-level data; QST measures were contrasted between healthy and osteoarthritic cats. Four bibliographic databases were searched; quality and risk of bias assessment were performed using pre-established criteria.
RESULTS
Six articles were included; most were of high quality and low risk of bias. Punctate tactile threshold (n = 70) and mechanical temporal summation (n = 35) were eligible for analysis. Cats with OA have lower punctate tactile threshold [mean difference (95%HDI): -44 (-60; -26) grams] and facilitated temporal summation of pain [hazard ratio (95%HDI): 5.32 (2.19; 14) times] when compared with healthy cats. The effect of sex and body weight on sensory sensitivity remained inconclusive throughout all analyses. Due to the correlation between age and OA status, it remains difficult to assess the effect of OA on sensory sensitivity, independently of age.
CONCLUSIONS
Clear and transparent reporting using guidelines are warranted. Similar to people, centralized sensitization is a feature of OA in cats. Future studies should try to elucidate the age effect on feline OA. Research with natural OA in cats is promising with potential to benefit feline health and welfare, and improve translatability to clinical research.
Topics: Animals; Arthralgia; Cats; Central Nervous System Sensitization; Osteoarthritis; Postsynaptic Potential Summation; Sensory Thresholds
PubMed: 32360738
DOI: 10.1016/j.joca.2020.04.006 -
Frontiers in Neuroendocrinology Apr 2020Endocrine organizational and activational influences on cognitive and affective circuits are likely critical to the development of premenstrual dysphoric disorder...
Endocrine organizational and activational influences on cognitive and affective circuits are likely critical to the development of premenstrual dysphoric disorder (PMDD), a sex-specific hormone-dependent mood disorder. An overview of the anatomical and functional neural characterization of this disorder is presented here by means of neuroimaging correlates, identified from eighteen publications (n = 361 subjects). While white matter integrity remains uninvestigated, greater cerebellar grey matter volume and metabolism were observed in patients with PMDD, along with altered serotonergic and GABAergic neurotransmission. Differential corticolimbic activation in response to emotional stimuli distinguishes the PMDD brain, namely enhanced amygdalar and diminished fronto-cortical function. Thus far, the emotional distress and dysregulation linked to PMDD seem to be defined by structural, chemical and functional brain signatures; however, their characterization remains sparsely studied and somewhat inconsistent. Clear and well-replicated neurobiological features of PMDD are needed to promote timely diagnoses and inform development of prevention and treatment strategies.
Topics: Adult; Brain; Cognition; Emotions; Female; Humans; Magnetic Resonance Imaging; Menstrual Cycle; Neuroimaging; Positron-Emission Tomography; Premenstrual Dysphoric Disorder; Serotonin; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 32268180
DOI: 10.1016/j.yfrne.2020.100838