β2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure.
Rodriguez Cruz, Pedro M
Brain : a journal of neurology
Oxford University Press (OUP)
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Vanhaesebrouck, A., Webster, R., Maxwell, S., Rodriguez Cruz, P. M., Cossins, J., Wickens, J., Liu, W., et al. (2019). β2-Adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure.. Brain : a journal of neurology, 142 (12), 3713-3727. https://doi.org/10.1093/brain/awz322
Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.
Neuromuscular Junction, Animals, Humans, Mice, Myasthenic Syndromes, Congenital, Disease Models, Animal, Albuterol, Pyridostigmine Bromide, Cholinesterase Inhibitors, Synaptic Transmission, Action Potentials, Adrenergic beta-2 Receptor Agonists
This work was mainly funded through a Wellcome trust clinical research training fellowship to A.V. 103406/Z/13/Z. Additional funding was obtained from MRC programme grant MR/M006824 (D.B).
External DOI: https://doi.org/10.1093/brain/awz322
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298046
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/