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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 -
Frontiers in Psychiatry 2022Obsessive-compulsive disorder (OCD) is a highly prevalent chronic disorder, often refractory to treatment. While remaining elusive, a full understanding of the...
INTRODUCTION
Obsessive-compulsive disorder (OCD) is a highly prevalent chronic disorder, often refractory to treatment. While remaining elusive, a full understanding of the pathophysiology of OCD is crucial to optimize treatment. Transcranial magnetic stimulation (TMS) is a non-invasive technique that, paired with other neurophysiological techniques, such as electromyography, allows for assessment of human corticospinal neurophysiology. It has been used in clinical populations, including comparisons of patients with OCD and control volunteers. Results are often contradictory, and it is unclear if such measures change after treatment. Here we summarize research comparing corticospinal excitability between patients with OCD and control volunteers, and explore the effects of treatment with repetitive TMS (rTMS) on these excitability measures.
METHODS
We conducted a systematic review and meta-analysis of case-control studies comparing various motor cortical excitability measures in patients with OCD and control volunteers. Whenever possible, we meta-analyzed motor cortical excitability changes after rTMS treatment.
RESULTS
From 1,282 articles, 17 reporting motor cortex excitability measures were included in quantitative analyses. Meta-analysis regarding cortical silent period shows inhibitory deficits in patients with OCD, when compared to control volunteers. We found no statistically significant differences in the remaining meta-analyses, and no evidence, in patients with OCD, of pre- to post-rTMS changes in resting motor threshold, the only excitability measure for which longitudinal data were reported.
DISCUSSION
Our work suggests an inhibitory deficit of motor cortex excitability in patients with OCD when compared to control volunteers. Cortical silent period is believed to reflect activity of GABA receptors, which is in line with neuroimaging research, showing GABAergic deficits in patients with OCD. Regardless of its effect on OCD symptoms, rTMS apparently does not modify Resting Motor Threshold, possibly because this measure reflects glutamatergic synaptic transmission, while rTMS is believed to mainly influence GABAergic function. Our meta-analyses are limited by the small number of studies included, and their methodological heterogeneity. Nonetheless, cortical silent period is a reliable and easily implementable measurement to assess neurophysiology in humans, . The present review illustrates the importance of pursuing the study of OCD pathophysiology using cortical silent period and other easily accessible, non-invasive measures of cortical excitability.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020201764], identifier [CRD42020201764].
PubMed: 36569621
DOI: 10.3389/fpsyt.2022.1050480 -
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 -
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 -
Sensors (Basel, Switzerland) Jul 2014The evoked electromyographic signal (eEMG) potential is the standard index used to monitor both electrical changes within the motor unit during muscular activity and the... (Review)
Review
The evoked electromyographic signal (eEMG) potential is the standard index used to monitor both electrical changes within the motor unit during muscular activity and the electrical patterns during evoked contraction. However, technical and physiological limitations often preclude the acquisition and analysis of the signal especially during functional electrical stimulation (FES)-evoked contractions. Hence, an accurate quantification of the relationship between the eEMG potential and FES-evoked muscle response remains elusive and continues to attract the attention of researchers due to its potential application in the fields of biomechanics, muscle physiology, and rehabilitation science. We conducted a systematic review to examine the effectiveness of eEMG potentials to assess muscle force and fatigue, particularly as a biofeedback descriptor of FES-evoked contractions in individuals with spinal cord injury. At the outset, 2867 citations were identified and, finally, fifty-nine trials met the inclusion criteria. Four hypotheses were proposed and evaluated to inform this review. The results showed that eEMG is effective at quantifying muscle force and fatigue during isometric contraction, but may not be effective during dynamic contractions including cycling and stepping. Positive correlation of up to r = 0.90 (p < 0.05) between the decline in the peak-to-peak amplitude of the eEMG and the decline in the force output during fatiguing isometric contractions has been reported. In the available prediction models, the performance index of the eEMG signal to estimate the generated muscle force ranged from 3.8% to 34% for 18 s to 70 s ahead of the actual muscle force generation. The strength and inherent limitations of the eEMG signal to assess muscle force and fatigue were evident from our findings with implications in clinical management of spinal cord injury (SCI) population.
Topics: Electromyography; Evidence-Based Medicine; Humans; Muscle Contraction; Muscle Fatigue; Muscle Strength; Muscle, Skeletal; Neuromuscular Junction; Spinal Cord Injuries; Spinal Cord Stimulation; Synaptic Transmission
PubMed: 25025551
DOI: 10.3390/s140712598 -
International Journal of Molecular... Jan 2024X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with... (Review)
Review
X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE's risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.
Topics: Male; Humans; Animals; Mice; Retinoschisis; Retina; Electroretinography; Genetic Therapy; Mutation; Eye Proteins
PubMed: 38279267
DOI: 10.3390/ijms25021267 -
Molecular Psychiatry Oct 2015Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although... (Meta-Analysis)
Meta-Analysis Review
Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.
Topics: Cognition Disorders; Double-Blind Method; Excitatory Amino Acid Agents; Humans; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission
PubMed: 26077694
DOI: 10.1038/mp.2015.68 -
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 -
Psychopharmacology Nov 2019While cannabis-based medicinal products have been shown to be effective for numerous neurological and psychiatric disorders, the evidence base regarding their adverse... (Meta-Analysis)
Meta-Analysis
RATIONALE
While cannabis-based medicinal products have been shown to be effective for numerous neurological and psychiatric disorders, the evidence base regarding their adverse cognitive effects is poorly understood. The cannabinoid 1 receptor modulates memory performance via intracellular and extracellular mechanisms that alter synaptic transmission and plasticity. While previous literature has consistently shown that chronic cannabis users exhibit marked cognitive impairments, mixed findings have been reported in the context of placebo-controlled experimental trials. It is therefore unclear whether these compounds inherently alter cognitive processes or whether individuals who are genetically predisposed to use cannabis may have underlying cognitive deficits.
OBJECTIVE
We conducted a meta-analysis to investigate the effects of full and partial cannabinoid 1 receptor (CB1R) agonists, antagonists, and negative allosteric modulators on non-spatial and spatial memory.
METHODS
In accordance with the PRISMA guidelines, the EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining the effects of CB1R agonists, antagonists, and negative allosteric modulators on memory performance.
RESULTS
We systematically reviewed 195 studies investigating the effects of cannabinoid compounds on memory. In humans (N = 35 studies, comprising N = 782 subjects), delta-9-tetrahydrocannabinol (THC) (1.5-5 mg/kg) relative to placebo impaired performance on non-spatial memory tests, whereas only high THC doses (67 mg/kg) impaired spatial memory. Similarly, THC (0.2-4 mg/kg) significantly impaired visuospatial memory in monkeys and non-human primates (N = 8 studies, comprising N = 71 subjects). However, acute THC (0.002-10 mg/kg) had no effect on non-spatial (N = 6 studies, comprising 117 subjects; g = 1.72, 95% confidence interval (CI) - 0.18 to 3.63, p = 0.08) or spatial memory (9 studies, comprising 206 subjects; g = 0.75, 95% confidence interval (CI) - 1.09 to 2.58, p = 0.43). However, acute, full CB1R agonists significantly impaired non-spatial memory (N = 23 studies, 519 subjects; g = - 1.39, 95% CI - 2.72 to - 0.06, p = 0.03). By contrast, the chronic administration of CB1R agonists had no effect on non-spatial memory (N = 5 studies, comprising 146 subjects; g = - 0.05, 95% confidence interval (CI) - 1.32 to 1.22, p = 0.94). Moreover, the acute administration of CB1R antagonists had no effect on non-spatial memory in rodents (N = 9 studies, N = 149 subjects; g = 0.40, 95% CI - 0.11 to 0.92, p = 0.12).
CONCLUSIONS
The acute administration of THC, partial CB1R agonist, significantly impaired non-spatial memory in humans, monkeys, and non-human primates but not rodents. However, full CB1R agonists significantly impaired non-spatial memory in a dose-dependent manner but CB1R antagonists had no effect on non-spatial memory in rodents. Moreover, chronic THC administration did not significantly impair spatial or non-spatial memory in rodents, and there is inconclusive evidence on this in humans. Our findings highlight species differences in the effects of cannabinoid compounds on memory.
Topics: Animals; Cannabinoids; Cognition; Cognition Disorders; Dronabinol; Humans; Memory; Receptor, Cannabinoid, CB1; Species Specificity; Synaptic Transmission
PubMed: 31165913
DOI: 10.1007/s00213-019-05283-3