China
Africa
Explore chapters and articles related to this topic
Cholinergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Vishal S. Gulecha, Manoj S. Mahajan, Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
These are the agents that competitively antagonize the action of ACh at the postsynaptic nicotinic receptor (Fig. 2.2). This is a dynamic binding that allows association and dissociation, that is, increased the concentration of ACh than the antagonist results in receptor occupation. With blockade by antagonist, endplate potential decreases gradually until it fails to reach the threshold to generate propagating action potential needed for muscle contraction. Under normal physiological conditions, more transmitter molecules than are needed to generate the endplate potential, evoking a greater than needed response. Simultaneously, only a fraction of the available receptors is used to generate the signal. Neuromuscular transmission, therefore, has a substantial margin of safety (Donati and Bevan, 1996).
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
The release of ACh by a nerve stimulus can be recorded by electrophysiological methods with good time resolution, provided that the experimental conditions are adjusted with care. A problem that arises with electrophysiological recordings is that upon stimulation of the nerve under normal conditions neuromuscular transmission occurs and the standard spike of the muscle fiber overshadows the electric effect proper of the released neurotransmitter; moreover, the muscle contraction that follows dislodges the microelectrode from the impaled cell. Only when the depolarization caused by the openings of the transmitter receptor channels is reduced below the firing threshold of the muscle fiber it is possible to monitor the so-called “endplate potential” (EPP). In principle, muscle spikes can be avoided or prevented by one of the following methods (see also Glavinovic’57 for the evaluation of the pro’s and contra’s): (1) attenuation of the size of the EPP by application of curare which blocks the AChRs, (2) reduction of the quantal content by exposing the muscle to a low ratio of Ca2+/Mg2+ in the medium, (3) cutting the fibers not far away from the endplates (the “cut muscle” preparation). The resulting steady depolarization of the muscle stumps (around -35 mV) causes inactivation of the voltage-dependent Na+ channels of the muscle fiber, and (4) treating the preparation with μ-conotoxin. This substance prevents muscle spikes by blocking Na+ channels of the muscle without blocking those of the nerve.
Skeletal Muscle
Published in Manoj Ramachandran, Tom Nunn, Basic Orthopaedic Sciences, 2018
Mike Fox, Steve Key, Simon Lambert
Depolarization is dependent on the amount of ACh released into the synaptic cleft. Depolarization is also dependent on the rate of release of ACh into the cleft, as it is broken down rapidly by cholinesterases from the post-synaptic membrane. When the end-plate potential exceeds its threshold, an action potential will be initiated within the muscle fibre by activation of voltage-gated Na+ channels. This muscle fibre action potential propagates through the sarcolemma in an identical manner to the nerve action potential.
Advances in autoimmune myasthenia gravis management
Published in Expert Review of Neurotherapeutics, 2018
Shuhui Wang, Iva Breskovska, Shreya Gandhy, Anna Rostedt Punga, Jeffery T. Guptill, Henry J. Kaminski
Regardless of the autoantibody type, the underlying physiological abnormality leading to skeletal muscle weakness is the reduction of the safety factor for neuromuscular transmission [29,30]. The safety factor is the difference in the endplate potential and the threshold potential required to generate an action potential, which will then trigger contraction of the muscle fiber. Whether there are AChR, MuSK, or no other autoantibody presently detected, the reduction of AChR is the primary contributor to a reduced endplate potential. Loss of synaptic folds and post-synaptic sodium channels serve to reduce the safety factor further. This tenuous situation of low safety factors among neuromuscular junctions across all skeletal muscle in a patient leads to the variability in weakness depending on the level of activity, degree of damage, temperature, and unknown factors produces the characteristic fatigable weakness that patients experience. Repetitive neuronal activity leads to a small reduction in release of acetylcholine, which under normal conditions is unimportant, but at the myasthenic junction can reduce the endplate potential that is required for action potential generation with consequent reduced muscle force generation and weakness. The basal lamina of the synaptic cleft is concentrated with acetylcholinesterase (AChE), which serves to terminate the activity of acetylcholine released from the presynaptic nerve terminal. AChE inhibition increases the available acetylcholine for binding to the AChR, thereby increasing the endplate potential and improving a compromise of the safety factor.
Sensory neurotization of muscle: past, present and future considerations
Published in Journal of Plastic Surgery and Hand Surgery, 2019
Steven D. Kozusko, Alexander J. Kaminsky, Louisa C. Boyd, Petros Konofaos
There are a few contraindications reported for sensory neurotization. If the period of denervation time is substantial then permanent muscle atrophy with loss of end-plate potential precludes efficacy of sensory neurotization. If the muscle has been severely damaged and restoration of neuronal input would have no functional recovery then sensory neurotization is inappropriate. Lastly, if the extremity is severely damaged or there is marked joint stiffness and fibrotic muscles then sensory neurotization would not provide substantial benefit [27].
Review of the mechanism underlying mefloquine-induced neurotoxicity
Published in Critical Reviews in Toxicology, 2021
Airton C. Martins, Monica M. B. Paoliello, Anca O. Docea, Abel Santamaria, Alexey A. Tinkov, Anatoly V. Skalny, Michael Aschner
The proposed role of altered Ca2+ homeostasis in mefloquine-induced neurotoxicity, and its relationship to other pathogenetic mechanisms are shown in Figure 2. Mefloquine has been found to be a noncompetitive inhibitor of both acetylcholinesterase (AChE, located in neural synapses), and butyrylcholinesterase (BChE, located in the liver and blood) (Lim and Go 1985). Inhibition of AChE alters both peripheral and central cholinergic synaptic transmission. AChE catalyzes the hydrolysis of acetylcholine to acetate and choline to clear acetylcholine from the cholinergic synapse, attenuating neurotransmission. Inhibition of acetylcholinesterase by mefloquine prolongs the stimulation of muscarinic or nicotinic acetylcholine receptors, disrupting neurotransmission. Indeed, mefloquine significantly increases mean miniature endplate potential (MEPP) frequency, increases MEPP amplitude, and prolongs its duration at the neuromuscular junction at minimum mefloquine concentration of 10 μM (McArdle et al. 2005, 2006), suggesting that mefloquine may contribute to neurotoxicity through altered cholinergic synaptic transmission. The prolonged neurotransmission by acetylcholine may be responsible for the disruption of calcium (Ca2+) homeostasis, resulting in neurotoxic effects. Acetylcholine binds and interacts with nicotinic (nAChR) and muscarinic acetylcholine receptors (mAChR), which results in increased intracellular Ca2+concentrations. nAChRs are ionotropic receptors that bind acetylcholine and are permeable to sodium, potassium, and Ca2+ (Siegel et al. 1999) (Figure 2). mAChRs bind acetylcholine and induce the catalysis of inositol 1,4,5-triphosphate (IP3) by phospholipase C (PLC) or the catalysis of cyclic adenosine monophosphate (cAMP) by adenylate cyclase (Siegel et al. 1999). These second messengers regulate Ca2+ homeostasis via modulation of plasma membrane and endoplasmic reticulum membrane ion channels (Figure 2). Traditionally, AChE inhibition and disruption of Ca2+ homeostasis have been associated with memory deficit, seizures, and neurodegeneration of hippocampal pyramidal neurons (Ijomone et al. 2019). These observations are consistent with earlier reported associations, showing that anticholinesterase agents not only induce neurodegeneration of pyramidal neurons residing in CA1 hippocampal area, but also potentiated neuronal oxidative damage (Gupta et al. 2007).