acetyl choline
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Toxins ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 53
Author(s):  
Hodan Ibrahim ◽  
Jacquie Maignel ◽  
Fraser Hornby ◽  
Donna Daly ◽  
Matthew Beard

Botulinum neurotoxin (BoNT/A) is an FDA and NICE approved second-line treatment for overactive bladder (OAB) in patients either not responsive or intolerant to anti-cholinergic drugs. BoNT/A acts to weaken muscle contraction by blocking release of the neurotransmitter acetyl choline (ACh) at neuromuscular junctions. However, this biological activity does not easily explain all the observed effects in clinical and non-clinical studies. There are also conflicting reports of expression of the BoNT/A protein receptor, SV2, and intracellular target protein, SNAP-25, in the urothelium and bladder. This review presents the current evidence of BoNT/A’s effect on bladder sensation, potential mechanisms by which it might exert these effects and discusses recent advances in understanding the action of BoNT in bladder tissue.


2021 ◽  
Vol 23 ◽  
Author(s):  
Concetta Cafiero ◽  
Alessandra Micera ◽  
Agnese Re ◽  
Loredana Postiglione ◽  
Andrea Cacciamani ◽  
...  

: SARS-CoV-2 pathogenesis has been recently extended to human central nervous system (CNS), in addition to nasopharyngeal truck, eye, lung and gut. The recent literature highlights that some SARS-CoV-2 spike glycoprotein regions homologous to neurotoxin-like peptides might bind to human nicotinic Acetyl-Choline Receptors (nAChRs). Spike-nAChR interaction can probably cause dysregulation of CNS and cholinergic anti-inflammatory pathways and uncontrolled immune-response, both associated to a severe COVID-19 pathophysiology. Herein, we hypothesize that inside the Open Reading Frame (ORF) region of spike glycoprotein, the RNA polymerase can translate small neurotoxic peptides by means of a “jumping mechanism” already demonstrated in other coronaviruses. These small peptides can bind the snAChRs instead of Spike glycoproteins. A striking homology occurred between these small peptides observed by sequence retrieval and proteins alignment. Acting as nAChRs antagonists, these small peptides (conotoxins) could be the explanation for the extrapulmonary clinical manifestations (neurological, hemorrhagic and thrombotic expressions, the prolonged apnea, the cardiocirculatory collapse, the heart arrhythmias, the ventricular tachycardia, the body temperature alteration, the electrolyte K+ imbalance and finally the significant reduction of butyryl cholinesterase (BuChE) plasma levels, as observed in COVID-19 patients. Several factors might induce the expression of these small peptides, including microbiota. The main hypothesis regarding the presence of these small peptides opens a new scenario on the etiology of COVID-19 clinical symptoms observed so far, including the neurological manifestations.


Author(s):  
Manar E. Khalifa ◽  
Leonie Unterholzner ◽  
Muhammad Munir

Rabies represents a typical model for spillover of zoonotic viral diseases among multiple hosts. Understanding the success of rabies virus (RV) in switching hosts requires the analysis of viral evolution and host interactions. In this study, we have investigated the structural and sequence analysis of host receptors among different RV susceptible host species. Our extensive bioinformatic analysis revealed the absence of the integrin plexin domain in the integrin β1 (ITGB1) receptor of the black fruit bats in the current annotation of the genome. Interestingly, the nicotinic acetyl choline receptor (nAChR) interaction site with the glycoprotein (G) of RV was conserved among different species. To study the interaction dynamics between RV-G protein and the RV receptors, we constructed and analyzed structures of RV receptors and G proteins using homology modeling. The molecular docking of protein-protein interaction between RV-G protein and different host receptors highlighted the variability of interacting residues between RV receptors of different species. These in silico structural analysis and interaction mapping of viral protein and host receptors establish the foundation to understand complex entry mechanisms of RV entry, which may facilitate the understanding of receptor mediated spillover events in RV infections and guide the development of novel vaccines to contain the infection.


2021 ◽  
Vol 12 ◽  
Author(s):  
Young-Soo Han ◽  
Philippe Delmotte ◽  
Gary C. Sieck

Previously, we reported that in airway smooth muscle (ASM), the cytosolic Ca2+ ([Ca2+]cyt) and force response induced by acetyl choline (ACh) are increased by exposure to the pro-inflammatory cytokine tumor necrosis factor α (TNFα). The increase in ASM force induced by TNFα was not associated with an increase in regulatory myosin light chain (rMLC20) phosphorylation but was associated with an increase in contractile protein (actin and myosin) concentration and an enhancement of Ca2+ dependent actin polymerization. The sensitivity of ASM force generation to elevated [Ca2+]cyt (Ca2+ sensitivity) is dynamic involving both the shorter-term canonical calmodulin-myosin light chain kinase (MLCK) signaling cascade that regulates rMLC20 phosphorylation and cross-bridge recruitment as well as the longer-term regulation of actin polymerization that regulates contractile unit recruitment and actin tethering to the cortical cytoskeleton. In this study, we simultaneously measured [Ca2+]cyt and force responses to ACh and explored the impact of 24-h TNFα on the dynamic relationship between [Ca2+]cyt and force responses. The temporal delay between the onset of [Ca2+]cyt and force responses was not affected by TNFα. Similarly, the rates of rise of [Ca2+]cyt and force responses were not affected by TNFα. The absence of an impact of TNFα on the short delay relationships between [Ca2+]cyt and force was consistent with the absence of an effect of [Ca2+]cyt and force on rMLC20 phosphorylation. However, the integral of the phase-loop plot of [Ca2+]cyt and force increased with TNFα, consistent with an impact on actin polymerization and, contractile unit recruitment and actin tethering to the cortical cytoskeleton.


Dysphagia ◽  
2021 ◽  
Author(s):  
Panos Stathopoulos ◽  
Marinos C. Dalakas

AbstractAutoimmune neurogenic dysphagia refers to manifestation of dysphagia due to autoimmune diseases affecting muscle, neuromuscular junction, nerves, roots, brainstem, or cortex. Dysphagia is either part of the evolving clinical symptomatology of an underlying neurological autoimmunity or occurs as a sole manifestation, acutely or insidiously. This opinion article reviews the autoimmune neurological causes of dysphagia, highlights clinical clues and laboratory testing that facilitate early diagnosis, especially when dysphagia is the presenting symptom, and outlines the most effective immunotherapeutic approaches. Dysphagia is common in inflammatory myopathies, most prominently in inclusion body myositis, and is frequent in myasthenia gravis, occurring early in bulbar-onset disease or during the course of progressive, generalized disease. Acute-onset dysphagia is often seen in Guillain–Barre syndrome variants and slowly progressive dysphagia in paraneoplastic neuropathies highlighted by the presence of specific autoantibodies. The most common causes of CNS autoimmune dysphagia are demyelinating and inflammatory lesions in the brainstem, occurring in patients with multiple sclerosis and neuromyelitis optica spectrum disorders. Less common, but often overlooked, is dysphagia in stiff-person syndrome especially in conjunction with cerebellar ataxia and high anti-GAD autoantibodies, and in gastrointestinal dysmotility syndromes associated with autoantibodies against the ganglionic acetyl-choline receptor. In the setting of many neurological autoimmunities, acute-onset or progressive dysphagia is a potentially treatable condition, requiring increased awareness for prompt diagnosis and early immunotherapy initiation.


2021 ◽  
Vol 5 (3) ◽  
pp. 019-023
Author(s):  
Nusrat Aziz

Botulinum toxin is produced by Clostridium botulini bacteria. It has been increasingly used as a boon in medical practice for chemodenervation in conditions like skeletal muscle spasticity, glandular hypersecretion, neuropathic pain and smooth muscle hyperactivity. The action of Botulinum neurotoxin (BoNT) is by blocking the neurotransmission at the cholinergic nerve endings, by inhibiting the docking and fusion of Acetyl Choline (Ach) vesicles for exocytosis into the synaptic area.Botulinum toxin has been used for management of neurological disorders with great patient satisfaction and appreciation. The effect of botulinum toxin wears off in 3-6 months and may require another dose. Frequent dosing may lead to production of antibodies against BoNT with consequent irresponsiveness to therapy in a few cases. Scrupulous use of botulinum toxin in the hands of experts may help a long way in giving much needed relief and respite to neurological patients and increase their quality of life. Its use in cosmetic dermatology in reducing wrinkles, by relaxing the facial muscles is very popular


2021 ◽  
Vol 13 ◽  
Author(s):  
Estibaliz Etxeberria-Rekalde ◽  
Saioa Alzola-Aldamizetxebarria ◽  
Stefanie Flunkert ◽  
Isabella Hable ◽  
Magdalena Daurer ◽  
...  

Huntington’s disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used. The R6/2 mouse as model of HD was already shown to present major neuropathological changes in the caudate putamen and other brain regions, but recently established biomarkers in HD patients were yet not analyzed in these mice. We therefore performed an in-depth analysis of R6/2 mice to establish new and highly translational readouts focusing on Ctip2 as biological marker for motor system-related neurons and translocator protein (TSPO) as a promising readout for early neuroinflammation. Our results validate already shown pathologies like mutant huntingtin aggregates, ubiquitination, and brain atrophy, but also provide evidence for decreased tyrosine hydroxylase and Ctip2 levels as indicators of a disturbed motor system, while vesicular acetyl choline transporter levels as marker for the cholinergic system barely change. Additionally, increased astrocytosis and activated microglia were observed by GFAP, Iba1 and TSPO labeling, illustrating, that TSPO is a more sensitive marker for early neuroinflammation compared to GFAP and Iba1. Our results thus demonstrate a high sensitivity and translational value of Ctip2 and TSPO as new marker for the preclinical evaluation of new compounds in the R6/2 mouse model of HD.


Author(s):  
Naoya Takeda ◽  
Keisuke Hirata ◽  
Kazuya Tsuruta ◽  
Garrett D. Santis ◽  
XS Sotiris ◽  
...  

The infrared (IR) spectra of gas phase protonated nicotine has been measured in the never-before probed N-H “fingerprint region” (3,200–3,500 cm−1). The protonated molecules generated by an electrospray source are...


2020 ◽  
Vol 11 ◽  
Author(s):  
Ahmad Alwazzan ◽  
Riffat Mehboob ◽  
Syed Amir Gilani ◽  
Amber Hassan ◽  
Shahida Perveen ◽  
...  

Preeclampsia (PE) and gestational diabetes (GD) are complications in advanced pregnancy while miscarriage for early pregnancy. However, the etiological factors are not well understood. Smoking has been associated with these complications as well as the sudden intrauterine deaths, sudden infant death, miscarriages, and still births. However, the immunolocalization of alpha 7 nicotine acetylcholine receptor (α7-nAChR) is not studied.Materials and Methods: α7-nAChR subunit expression was evaluated in 10 paraffin-embedded placental tissues after delivery and 10 tissue samples of products of conception during first trimester by immunohistochemistry. Among the placental tissues, two samples were normal placental tissue, four from PE mother, and four from GD mother. The expression of α7-nAChR was compared between the two groups in general and within the subgroups of placenta as well. Protein expression was evaluated using the nuclear labeling index (%) of villi with positive cells stained, positive cells in the decidua, and intensity of staining in the outer villous trophoblast layer.Results: The expression of α7-nAChR protein was high in all the cases of placenta and products of conception (POCs). α7-nAChR expression showed no notable differences among different cases of miscarriages irrespective of the mother’s age and gestational age at which the event occurred. However, there were some changes among the normal, PE, and GD placental groups in the linings of the blood vessels. Changes were restricted to the villi (as opposed to the decidua) lining cells, both cytotrophoblast and syncytiotrophoblast, and were specific to the α7 subunit. PE blood vessel lining was thicker and showed more expression of this receptor in endothelial cells and myofibroblasts in PE and GD groups. In POCs, the strong expression was observed in the decidua myocytes of maternal blood vessels and in syncytiotrophoblast and cytotrophoblast of chronic villi.Conclusion: Nicotine acetyl choline receptors are found to be expressed highly in the placental tissues and in products of conception. They may be associated with the sudden perinatal deaths and miscarriages or complications of pregnancy.


2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Muhammad Kamran ◽  
Rehana Kousar ◽  
Shakir Ullah ◽  
Siraj Khan ◽  
Muhammad Farooq Umer ◽  
...  

Alzheimer’s disease (AD) is a neurodegenerative disorder manifested by decline in memory and mild cognitive impairment leading to dementia. Despite global occurrence of AD, the severity and hence onset of dementia vary among different regions, which was correlated with the customary use of medicinal herbs and exposure level to the causatives. In spite of execution of versatile therapeutic strategies to combat AD and other neurodegenerative diseases, success is only limited to symptomatic treatment. The role of natural remedies remained primitive and irreplaceable in all ages. In some examples, the extracted drugs failed to show comparable results due to lack of micro ingredients. Micro ingredients impart a peerless value to natural remedies which are difficult to isolate and/or determine their precise role during treatment. A variety of plants have been used for memory enhancement and other dementia-related complications since ages. Acetyl choline esterase inhibition, antioxidant potential, neuroprotection, mitochondrial energy restoration, and/or precipitated protein clearance put a vast taxonomic variety into a single group of anti-AD plants. Secondary metabolites derived from these medicinal plants have the potential to treat AD and other brain diseases of common pathology. This review summarizes the potential of taxonomically diverse medicinal plants in the treatment of AD serving as a guide to further exploration.


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