{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T01:10:10Z","timestamp":1777857010993,"version":"3.51.4"},"reference-count":50,"publisher":"SAGE Publications","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JND"],"published-print":{"date-parts":[[2021,9,14]]},"abstract":"<jats:p>Background In myasthenia gravis, impaired postsynaptic sensitivity to acetylcholine results in failure of neuromuscular transmission and fatiguing muscle weakness. Objective Develop 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. Methods Tubocurarine 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. Results Surprisingly, 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.<\/jats:p>","DOI":"10.3233\/jnd-210654","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T10:59:47Z","timestamp":1627642787000},"page":"831-844","source":"Crossref","is-referenced-by-count":0,"title":["The Safety Factor for Neuromuscular Transmission: Effects of Dimethylsulphoxide, Cannabinoids and Synaptic Homeostasis"],"prefix":"10.1177","volume":"8","author":[{"given":"Gianmaria Lorenzo","family":"Odierna","sequence":"first","affiliation":[{"name":"Discipline of Physiology and Bosch Institute, The University of Sydney, NSW, Australia"},{"name":"Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William Donald","family":"Phillips","sequence":"additional","affiliation":[{"name":"Discipline of Physiology and Bosch Institute, The University of Sydney, NSW, Australia"},{"name":"School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","reference":[{"key":"10.3233\/JND-210654_ref1","first-page":"874680","article-title":"Myasthenia gravis: A review","volume":"2012","author":"Jayam Trouth","year":"2012","journal-title":"Autoimmune Dis"},{"key":"10.3233\/JND-210654_ref2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jaut.2014.01.003","article-title":"Diagnostic and clinical classification of autoimmune myasthenia gravis","volume":"48-49","author":"Berrih-Aknin","year":"2014","journal-title":"J Autoimmun"},{"key":"10.3233\/JND-210654_ref3","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.autrev.2013.03.001","article-title":"Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4","volume":"12","author":"Verschuuren","year":"2013","journal-title":"Autoimmun Rev"},{"key":"10.3233\/JND-210654_ref4","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jaut.2013.12.011","article-title":"Myasthenia gravis: A comprehensive review of immune dysregulation and etiological mechanisms","volume":"52","author":"Berrih-Aknin","year":"2014","journal-title":"J Autoimmun"},{"key":"10.3233\/JND-210654_ref5","first-page":"1513","article-title":"Pathogenesis of myasthenia gravis: Update on disease types, models, and mechanisms","volume":"5","author":"Phillips","year":"2016","journal-title":"FResearch"},{"key":"10.3233\/JND-210654_ref6","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.autrev.2013.03.006","article-title":"Novel future therapeutic options in myasthenia gravis","volume":"12","author":"Dalakas","year":"2013","journal-title":"Autoimmunity Rev"},{"issue":"1","key":"10.3233\/JND-210654_ref7","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s13311-015-0398-y","article-title":"Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis","volume":"13","author":"Guptill","year":"2016","journal-title":"Neurotherapeutics"},{"key":"10.3233\/JND-210654_ref8","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.nmd.2019.12.003","article-title":"Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids","volume":"30","author":"Tannemaat","year":"2020","journal-title":"Neuromuscular Disorders"},{"key":"10.3233\/JND-210654_ref9","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/CND.0000000000000034","article-title":"Treatment-refractory myasthenia gravis","volume":"15","author":"Silvestri","year":"2014","journal-title":"J Clin Neuromuscul Dis"},{"issue":"5","key":"10.3233\/JND-210654_ref10","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/WCO.0000000000000136","article-title":"Clinical and scientific aspects of MuSK-related myasthenia gravis","volume":"27","author":"Reddel","year":"2014","journal-title":"Cur Opin Neurol"},{"key":"10.3233\/JND-210654_ref11","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3109\/08916930903518081","article-title":"Development of novel therapies for MG: Studies in animal models","volume":"43","author":"Souroujon","year":"2010","journal-title":"Autoimmunity"},{"key":"10.3233\/JND-210654_ref12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.expneurol.2015.05.001","article-title":"Editorial: Special issue on standardization of preclinical evaluation of animal models for myasthenia gravis","volume":"270","author":"Kusner","year":"2015","journal-title":"Exp Neurol"},{"issue":"18","key":"10.3233\/JND-210654_ref13","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.2174\/1381612821666150316123233","article-title":"Mouse Models of Myasthenia Gravis","volume":"21","author":"Ban","year":"2015","journal-title":"Curr Pharmaceutical Design"},{"issue":"2","key":"10.3233\/JND-210654_ref14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/0014-2999(67)90033-7","article-title":"The effect of triiodthyronine on neuromuscular junctions of isolated rat diaphragm","volume":"2","author":"Teitel","year":"1967","journal-title":"Euro J Pharmacol"},{"issue":"5","key":"10.3233\/JND-210654_ref15","doi-asserted-by":"crossref","first-page":"e2759","DOI":"10.21769\/BioProtoc.2759","article-title":"Mouse Phrenic Nerve Hemidiaphragm Assay (MPN)","volume":"8","author":"Zanetti","year":"2018","journal-title":"Bio-protocol"},{"issue":"5754","key":"10.3233\/JND-210654_ref16","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1126\/science.1120640","article-title":"Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures","volume":"310","author":"Rigoni","year":"2005","journal-title":"Science (New York, NY)"},{"issue":"1","key":"10.3233\/JND-210654_ref17","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/0006-8993(86)91209-6","article-title":"Curare can reverse the failure in muscle contraction caused by an AChE inhibitor","volume":"377","author":"Bradley","year":"1986","journal-title":"Brain Res"},{"issue":"Pt 4","key":"10.3233\/JND-210654_ref18","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1093\/brain\/aws025","article-title":"Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice","volume":"135","author":"Klooster","year":"2012","journal-title":"Brain"},{"issue":"8","key":"10.3233\/JND-210654_ref19","doi-asserted-by":"crossref","first-page":"e104081","DOI":"10.1371\/journal.pone.0104081","article-title":"Adenosine A2A receptors activation facilitates neuromuscular transmission in the pre-symptomatic phase of the SOD1(G93A) ALS mice, but not in the symptomatic phase","volume":"9","author":"Nascimento","year":"2014","journal-title":"PloS one"},{"key":"10.3233\/JND-210654_ref20","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S0301-0082(00)00055-1","article-title":"Safety factor at the neuromuscular junction","volume":"64","author":"Wood","year":"2001","journal-title":"Prog Neurobiol"},{"key":"10.3233\/JND-210654_ref21","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1001\/archneur.1975.00490500030002","article-title":"Guanidine and neuromuscular transmission. II. Effect on transmitter release in response to repetitive nerve stimulation","volume":"32","author":"Kamenskaya","year":"1975","journal-title":"Arch Neurol"},{"key":"10.3233\/JND-210654_ref22","doi-asserted-by":"crossref","unstructured":"Plomp JJ , Morsch M , Phillips WD , Verschuuren JJGM . Electrophysiological analysis of neuromuscular synaptic function in myasthenia gravis patients and animal models Exp Neurol 2015;270:41\u201354.","DOI":"10.1016\/j.expneurol.2015.01.007"},{"key":"10.3233\/JND-210654_ref23","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1113\/jphysiol.1992.sp019429","article-title":"Adaptation of quantal content to decreased postsynapitc sensitivity at single endplates in a-bungarotoxin-treated rats","volume":"458","author":"Plomp","year":"1992","journal-title":"J Physiol (Lond)"},{"key":"10.3233\/JND-210654_ref24","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.2741\/4532","article-title":"Trans-synaptic homeostasis at the myasthenic neuromuscular junction","volume":"22","author":"Plomp","year":"2017","journal-title":"Front Biosci (Landmark Ed)"},{"key":"10.3233\/JND-210654_ref25","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1146\/annurev-physiol-021014-071740","article-title":"Homeostatic control of presynaptic neurotransmitter release","volume":"77","author":"Davis","year":"2015","journal-title":"Annu Rev Physiol"},{"issue":"3","key":"10.3233\/JND-210654_ref26","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1523\/JNEUROSCI.3786-15.2016","article-title":"Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content","volume":"36","author":"Wang","year":"2016","journal-title":"J Neurosci"},{"key":"10.3233\/JND-210654_ref27","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.cophys.2018.06.007","article-title":"Rapid retrograde regulation of transmitter release at the NMJ","volume":"4","author":"Ribchester","year":"2018","journal-title":"Curr Opin Physiol"},{"issue":"2","key":"10.3233\/JND-210654_ref28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0014-2999(81)90411-8","article-title":"Effects of corticosteroids on neuromuscular blocking actions of d-tubocurarine","volume":"69","author":"Leeuwin","year":"1981","journal-title":"Euro J Pharmacology"},{"issue":"1","key":"10.3233\/JND-210654_ref30","first-page":"4685","article-title":"Cannabinoid-induced increase of quantal size and enhanced neuromuscular transmission","volume":"8","author":"Morsch","year":"2018","journal-title":"Sci Reports"},{"key":"10.3233\/JND-210654_ref31","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1113\/jphysiol.1981.sp013586","article-title":"Non-linear summation of end-plate potentials in the frog and mouse","volume":"311","author":"McLachlan","year":"1981","journal-title":"J Physiol"},{"issue":"1","key":"10.3233\/JND-210654_ref32","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0022-5193(76)80031-8","article-title":"The effect of membrane capacitance on non-linear summation of synaptic potentials","volume":"59","author":"Martin","year":"1976","journal-title":"J Theoretical biol"},{"issue":"8","key":"10.3233\/JND-210654_ref33","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0006-3495(76)85739-6","article-title":"A comment on Martin\u2019s relation","volume":"16","author":"Stevens","year":"1976","journal-title":"Biophysical Journal"},{"key":"10.3233\/JND-210654_ref34","doi-asserted-by":"crossref","unstructured":"Hennig MHs . Theoretical models of synaptic short term plasticity Front Comput Neurosci. 2013;7:154.","DOI":"10.3389\/fncom.2013.00154"},{"key":"10.3233\/JND-210654_ref35","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1055\/s-2004-829594","article-title":"Myasthenia gravis: Diagnosis","volume":"24","author":"Meriggioli","year":"2004","journal-title":"Semin Neurol"},{"key":"10.3233\/JND-210654_ref36","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1113\/jphysiol.1964.sp007495","article-title":"An electrophysiological investigation of neuromuscular transmission in myasthenia gravis","volume":"174","author":"Elmqvist","year":"1964","journal-title":"J Physiol (Lond)"},{"issue":"10","key":"10.3233\/JND-210654_ref37","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1113\/jphysiol.2013.251827","article-title":"Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody","volume":"591","author":"Morsch","year":"2013","journal-title":"J Physiol"},{"issue":"5","key":"10.3233\/JND-210654_ref38","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.physbeh.2007.03.027","article-title":"Forty mouse strain survey of voluntary calcium intake, blood calcium, and bone mineral content","volume":"91","author":"Tordoff","year":"2007","journal-title":"Physiol Behav"},{"key":"10.3233\/JND-210654_ref39","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1002\/mus.20751","article-title":"Safety factor for neuromuscular transmission at type-identified diaphragm fibers","volume":"35","author":"Ermilov","year":"2007","journal-title":"Muscle Nerve"},{"key":"10.3233\/JND-210654_ref40","first-page":"4641","article-title":"DMSO induces drastic changes in human cellular processes and epigenetic landscape in vitro","volume":"9","author":"Verheijen","year":"2019","journal-title":"Sci Reports"},{"issue":"5","key":"10.3233\/JND-210654_ref41","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/j.2042-7158.1972.tb09022.x","article-title":"Some actions of dimethylsulphoxide at the neuromuscular junction","volume":"24","author":"Gandiha","year":"1972","journal-title":"J Pharmacy and Pharmacol"},{"issue":"5060","key":"10.3233\/JND-210654_ref42","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/212405a0","article-title":"Cholinesterase inhibitory property of dimethyl sulphoxide","volume":"212","author":"Sams","year":"1966","journal-title":"Nature"},{"key":"10.3233\/JND-210654_ref43","unstructured":"McLarnon JG , Saint DA , Quastel DM . The actions of dimethyl sulfoxide on neuromuscular transmission Mol Pharmacol. 1986;30(6):631\u20138."},{"key":"10.3233\/JND-210654_ref44","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/0005-2736(85)90181-6","article-title":"The fusogenic substance dimethyl sulfoxide enhances exocytosis in motor nerve endings","volume":"819","author":"Geron","year":"1985","journal-title":"Biochim Biophys Acta"},{"key":"10.3233\/JND-210654_ref45","doi-asserted-by":"crossref","unstructured":"Majdi S , Najafinobar N , Dunevall J , Lovric J , Ewing AG . DMSO Chemically Alters Cell Membranes to Slow Exocytosis and Increase the Fraction of Partial Transmitter Released Chembiochem. 2017;18(19):1898\u2013902.","DOI":"10.1002\/cbic.201700410"},{"issue":"9","key":"10.3233\/JND-210654_ref46","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/0278-6915(93)90047-3","article-title":"Propylene glycol-induced skeletal muscle excitation","volume":"31","author":"Hattori","year":"1993","journal-title":"Food Chem Toxicol"},{"issue":"5","key":"10.3233\/JND-210654_ref47","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.neuron.2007.05.020","article-title":"Endocannabinoid-Mediated Long-Term Plasticity Requires cAMP\/PKA Signaling and RIM1\u03b1","volume":"54","author":"Chevaleyre","year":"2007","journal-title":"Neuron"},{"issue":"6828","key":"10.3233\/JND-210654_ref48","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/35069076","article-title":"Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses","volume":"410","author":"Wilson","year":"2001","journal-title":"Nature"},{"issue":"7","key":"10.3233\/JND-210654_ref49","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2183\/pjab.90.235","article-title":"Control of synaptic function by endocannabinoid-mediated retrograde signaling","volume":"90","author":"Kano","year":"2014","journal-title":"Proc Japan Acad Series B, Physical and Biological Sciences"},{"key":"10.3233\/JND-210654_ref50","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1113\/jphysiol.1979.sp013003","article-title":"The relationship between end-plate size and transmitter release in normal and dystrophic muscles of the mouse","volume":"296","author":"Harris","year":"1979","journal-title":"J Physiol (Lond)"},{"key":"10.3233\/JND-210654_ref51","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05473"}],"container-title":["Journal of Neuromuscular Diseases"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JND-210654","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T23:49:45Z","timestamp":1777506585000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JND-210654"}},"subtitle":[],"editor":[{"given":"Virginia","family":"Arechavala-Gomeza","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"Annemieke","family":"Aartsma-Rus","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,14]]},"references-count":50,"journal-issue":{"issue":"5"},"URL":"https:\/\/doi.org\/10.3233\/jnd-210654","relation":{},"ISSN":["2214-3599","2214-3602"],"issn-type":[{"value":"2214-3599","type":"print"},{"value":"2214-3602","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,14]]}}}