Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Issue title: The Null Hypothesis Stands
Guest editors: Virginia Arechavala-Gomeza and Annemieke Aartsma-Rus
Article type: Research Article
Authors: Odierna, Gianmaria Lorenzoa; b | Phillips, William Donalda; c; *
Affiliations: [a] Discipline of Physiology and Bosch Institute, The University of Sydney, NSW, Australia | [b] Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia | [c] School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia
Correspondence: [*] Correspondence to: Willian D. Phillips, School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia. Tel.: +61 433376472; E-mail: [email protected].
Abstract: BackgroundIn myasthenia gravis, impaired postsynaptic sensitivity to acetylcholine results in failure of neuromuscular transmission and fatiguing muscle weakness. ObjectiveDevelop an ex vivo muscle contraction assay to test cannabinoids and other substances that might act on the myasthenic neuromuscular junction to restore control of the muscle. MethodsTubocurarine was added to an ex vivo, mouse phrenic nerve-hemidiaphragm muscle preparation to reduce acetylcholine sensitivity. This produced a myasthenia-like decrement in twitch force during a train of 10 nerve impulses (3 / sec). Endplate potential (EPP) recordings were used to confirm and extend the findings. ResultsSurprisingly, addition to the bath of dimethylsulphoxide (DMSO), at concentrations as low as 0.1%(v/v), partially reversed the decrement in nerve-evoked force. Intracellular electrophysiology, conducted in the presence of tubocurarine, showed that DMSO increased the amplitudes of both the spontaneous miniature EPP (MEPP) and the (nerve-evoked) EPP. In the absence of tubocurarine (synaptic potentials at physiological levels), an adaptive fall in quantal content negated the DMSO-induced rise in EPP amplitude. The effects of cannabinoid receptor agonists (solubilized with DMSO) in the contraction assay do not support their further exploration as useful therapeutic agents for myasthenia gravis. CP 55,940 (a dual agonist for cannabinoid receptor types 1 and 2) reversed the beneficial effects of DMSO. Conclusions:We demonstrate a powerful effect of DMSO upon quantal amplitude that might mislead pharmacological studies of synaptic function wherever DMSO is used as a drug vehicle. Our results also show that compounds targeting impaired neuromuscular transmission should be tested under myasthenic-like conditions, so as to avoid confounding effects of synaptic homeostasis.
Keywords: Tubocurarine, DMSO, dimethylsulfoxide, solvents, cannabinoid receptors, synaptic transmission, muscle contraction, homeostasis, myasthenia gravis
DOI: 10.3233/JND-210654
Journal: Journal of Neuromuscular Diseases, vol. 8, no. 5, pp. 831-844, 2021
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
[email protected]
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]