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Peripheral Autonomic Neuropathies
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
The role of the nervous system in the maintenance of muscle is obvious and well documented. Acetylcholine, which is an established neurotransmitter at the neuromuscular junction, is necessary for trophic functions in the maintenance of muscle. But it is not clear whether an acetylcholine-mediated neuromuscular transmission alone is sufficient for trophic function in vitro or in vivo. In addition, there are other non-cholinergic factors that play a role in trophic activities, including axoplasmic flow. Some nerve trophic activity is closely related to adequate muscle contractions, as stimulation experiments show that usage alone can almost be sufficient to maintain muscle even if it is denervated. The spontaneous release of acetylcholine alone, however, is not sufficient for normal trophic function, but the possibility that it may contribute cannot be excluded.
Muscle
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
Myasthenia gravis is a condition that affects the neuromuscular junction. It is an autoimmune condition in which antibodies are produced against the post-synaptic acetylcholine receptors in the neuromuscular junction. When activated by acetylcholine, the postsynaptic acetylcholine receptors are associated with sodium channels that open and lead to depolarization of skeletal muscle. Immune-mediated destruction of these receptors results in an inability to contract skeletal muscles. Although myasthenia gravis can affect individuals of any age, it is more common in women under 40 years of age and men older than 60 years of age.
Henry Hallet Dale (1875–1968)
Published in Andrew P. Wickens, Key Thinkers in Neuroscience, 2018
To do this, Feldberg stimulated a given nerve in an animal and collected blood drawn from a nearby vein – hoping it would reveal the tiny amounts of acetylcholine when it was applied to the leech muscle. This method proved so successful that it pinpointed the sites of acetylcholine release throughout the peripheral nervous systems. It showed that acetylcholine was not only secreted by the endings of the parasympathetic nervous system but also at the synapse between the preganglionic and postganglionic fibres of the sympathetic system. Adding to this, acetylcholine was also confirmed as the neurotransmitter at the neuromuscular junction of skeletal muscles. In 1936, Dale and Loewi shared the Nobel Prize “for their discoveries relating to chemical transmission of nerve impulses”. It has been described as the greatest advance in neuroscience of the twentieth century. Even so, not all physiologists were won over by the concept of chemical neurotransmitters, and the issue would remain debateable until the mid-1950s, largely as a result of work undertaken by one of Dale’s adversaries – John Eccles.
Prospects for CAR T cell immunotherapy in autoimmune diseases: clues from Lupus
Published in Expert Opinion on Biological Therapy, 2022
Marko Radic, Indira Neeli, Tony Marion
Certain autoimmune diseases result from the effects of a single autoantibody specificity. Pemphigus is an autoimmune skin blistering disorder, in which autoantibodies play a central role. Most patients with pemphigus exhibit autoantibodies to desmoglein, a cadherin-like adhesion molecule that connects keratinocytes to each other and gives elasticity and cohesion to the epidermis [71]. Ellebrecht et al. [72] constructed CARs with extracellular domains derived from desmoglein to serve as ‘bait’ for anti-desmoglein B cells (Figure 3B). Upon binding to anti-desmoglein B cells, the redesigned chimeric autoantibody receptor (CAAR) triggers the specific killing of the autoreactive B cells. The success of this approach in animals provided preclinical data used in an application to the FDA for the initiation of clinical trials [73]. A similar approach has been developed for myasthenia gravis (MG), a progressive and debilitating disease with autoimmune disruption of acetylcholine receptor function at the neuromuscular junctions. A subset of patients with MG make autoantibodies to muscle signaling kinase (MuSK) and CAAR T cells using a portion of MuSK as the extracellular bait for autoreactive B cells are in early development (Oh S, 2020). Yet to be tested in the context of autoimmunity, a CAR T cell incorporating domains from a scavenging protein (Figure 3C) could offer an alternative approach to deplete excessive circulating IC, as shown by engineering in a phagocytic cell population [74].
Subchronic administration of Parastar insecticide induced behavioral changes and impaired motor coordination in male Wistar rats
Published in Drug and Chemical Toxicology, 2022
Antoine Kada Sanda, Akono Edouard Nantia, T. F. Pascal Manfo, Romi T. Toboh, Roxane Essame Abende, Sterling Adaibum, Paul Fewou Moundipa, Pierre Kamtchouing
The grip strength test is a functional method used to evaluate rat limb strength. This test has been used to investigate the effects of drug on neuromuscular disorders. In both Grid Suspension Grip-strength test and Wire Hang tests, Parastar decreased the suspension time, especially at the medium and high doses, and this suggests negative effect of the agrochemical on muscle strength and coordination in rats. Skeletal muscle contraction is mediated by acetylcholine at the neuromuscular junction. Therefore results from this study suggest a possible alteration of cholinergic neurons or acetylcholinesterase system by Parastar leading to neurotoxic effect. Khan et al. (2003) reported inhibition of brain cholinesterase following exposure of frogs to a component of Parastar, Lambda cyhalothrin. Other studies demonstrated the neurotoxic effect of another pesticide, Chlorpyrifos (Yumino et al.2002; Lee et al. 2014), which was attributed to the capacity of Chorpyrifos to enhance hydrogen peroxide levels (ROS), reduce the antioxidant potential of nervous system (Yumino et al.2002; Lee et al. 2014), and interrupt mitochondria activity in brain (Singh et al. 2013; Yamada et al. 2017). Parastar may induce neurotoxic effects through same or similar mechanism.
Emerging drugs for the treatment of myasthenia gravis
Published in Expert Opinion on Emerging Drugs, 2021
Deepak Menon, Alejandra Urra Pincheira, Vera Bril
Myasthenia gravis (MG) is an autoimmune disorder that affects signal transmission across the neuromuscular junction. As a result of impaired synaptic function, patients manifest with varying degrees of weakness affecting extraocular, facial, bulbar, respiratory and limb muscles. The weakness fluctuates with characteristic fatigability, worsening with effort and improving with rest. MG results from autoantibodies directed against post synaptic receptors setting in motion an inflammatory cascade directed against these receptors and ultimately leading to loss of function and destruction. In the majority of MG patients, these antibodies are directed against acetylcholine receptors (AChR). The other antibodies are directed against muscle-specific kinase (MUSK) and lipoprotein-related peptide (LRP4) receptors although as many as 15% are seronegative [1]. Thymic hyperplasia and thymoma are associated with AChR positive MG, implicating the thymus in MG pathogenesis.