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Abstract
Non-selective inhibitors of cholinesterases (ChEs) are clinically used for treatment of myasthenia gravis (MG). While being generally safe, they cause numerous adverse effects including induction of hyperactivity of urinary bladder and intestines affecting quality of patients life. In this study we have compared two ChEs inhibitors, a newly synthesized compound C547 and clinically used pyridostigmine bromide, by their efficiency to reduce muscle weakness symptoms and ability to activate contractions of urinary bladder in a rat model of autoimmune MG. We found that at dose effectively reducing MG symptoms, C547 did not affect activity of rat urinary bladder. In contrast, at equipotent dose, pyridostigmine caused a significant increase in tonus and force of spontaneous contractions of bladder wall. We also found that this profile of ChEs inhibitors translates into the preparation of human urinary bladder. The difference in action observed for C547 and pyridostigmine we attribute to a high level of pharmacological selectivity of C547 in inhibiting acetylcholinesterase as compared to butyrylcholinesterase. These results raise reasonable hope that selective acetylcholinesterase inhibitors should show efficacy in treating MG in human patients with a significant reduction in adverse effects related to hyperactivation of smooth muscles.
Highlights
Synaptic transmission at the skeletal neuromuscular junction (NMJ) is indispensable for survival of living organisms by transducing complexity of cerebral commands to muscular twitches
Experimental autoimmune myasthenia gravis (EAMG) was induced by rat immunization with a peptide analogous to an amino acid sequence derived from α-subunit of rat muscle type nicotinic acetylcholine receptors (nAChRs)
As it has been shown earlier[14,15], this type of rat EAMG resembles human myasthenia in the following aspects: (a) blood serum of affected animals contains antibodies toward muscle type nAChR; (b) there is a characteristic decrement in the amplitude of compound muscle action potential (AP) upon repetitive nerve stimulation as compared to normal animals
Summary
Synaptic transmission at the skeletal neuromuscular junction (NMJ) is indispensable for survival of living organisms by transducing complexity of cerebral commands to muscular twitches. We have described a series of cholinesterase inhibitors based on 1,3-bis[5-(o-nitrobenzy lethylammonium)pentyl]-6-methyluracilic unit with selectivity towards mammalian AChE vs BChE8–11 These inhibitors were found to be efficacious in an animal model of MG and can be considered as potentially valuable candidates for treatment of pathological muscle weakness syndromes in humans. Our experiments allow us to suggest that, after partial and selective inhibition of AChE, remaining activity of BChE in the urinary bladder is sufficient to prevent development of significant side effects. We made an important finding that sensitivity of human urinary bladder preparations to AChE and BChE inhibition is similar to that of the rat bladder This observation provides reasonable bases to hypothesize that remaining activity of BChE in urinary bladder in humans can be sufficient to reduce side effects when selective AChE inhibitors are used for MG treatment
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