In Situ Effects of Doxycycline on Neuromuscular Junction in Mice
Natália Tribuiani1, Jocimar de Souza1, Marcos Antônio de Queiroz Junior2
1Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Rodovia Raposo Tavares, 18023-000, Sorocaba, SP, Brazil.
Background:
The antibacterial mechanism of doxycycline is known, but its effects on the nerve-muscle system are still not unclear.
Objective:
The aim of the study was to combine molecular targets of the neuromuscular machinery using the in situ neuronal blocker effect of doxycycline, a semisynthetic second-generation tetracycline derivative, on mice neuromuscular preparations.
Methods:
The effects of doxycycline were assessed on presynaptic, synaptic cleft, and postsynaptic neurotransmission, along with the muscle fiber, using the traditional myographic technique. Precisely, the effects of doxycycline were categorized into "all" or "nothing" effects depending on the concentration of doxycycline used; "all" was obtained with 4 μM doxycycline, and "nothing" was obtained with 1-3 μM doxycycline. The rationale of this study was to apply known pharmacological tools against the blocker effect of 4 μM doxycycline, such as F55-6 (Casearia sylvestris), CaCl2 (or Ca2+), atropine, neostigmine, polyethylene glycol (PEG 400), and d-Tubocurarine. The evaluation of cholinesterase enzyme activity and the diaphragm muscle histology were performed, and protocols on the neuromuscular preparation submitted to indirect or direct stimuli were complementary.
Results:
Doxycycline does not affect cholinesterase activity nor causes damage to skeletal muscle diaphragm; it acts on ryanodine receptor, sarcolemmal membrane, and neuronal sodium channel with a postjunctional consequence due to the decreased availability of muscle nicotinic acetylcholine receptors.
Conclusion:
In conclusion, in addition to the neuronal blocker effect of doxycycline, we showed that doxycycline acts on multiple targets. It is antagonized by F55-6, a neuronal Na+-channel agonist, and Ca2+, but not by neostigmine.
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