Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Rodovia Raposo Tavares, 18023-000, Sorocaba, SP, Brazil.
Biomedicine Course, University of Sorocaba (UNISO), Rodovia Raposo Tavares, 18023-000, Sorocaba, SP, Brazil.
Curr Mol Med. 2022;22(4):349-353. doi: 10.2174/1566524021666210521125553.
The antibacterial mechanism of doxycycline is known, but its effects on the nerve-muscle system are still not unclear.
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.
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), CaCl (or Ca), 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.
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.
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 Ca, but not by neostigmine.
多西环素的抗菌机制已为人所知，但它对神经肌肉系统的影响仍不清楚。
本研究旨在结合神经肌肉机制的分子靶点，利用多西环素（一种半合成第二代四环素衍生物）对小鼠神经肌肉制剂的原位神经元阻断作用。
使用传统的肌电图技术评估多西环素对突触前、突触间隙和突触后神经传递以及肌肉纤维的影响。多西环素的作用分为“全有或全无”效应，具体取决于使用的多西环素浓度；4 μM 多西环素产生“全有”效应，1-3 μM 多西环素产生“全无”效应。本研究的原理是应用已知的药理学工具来对抗 4 μM 多西环素的阻断作用，如 F55-6（Casearia sylvestris）、CaCl（或 Ca）、阿托品、新斯的明、聚乙二醇（PEG 400）和 d-筒箭毒碱。评估了胆碱酯酶活性和膈神经肌肉组织学，并对接受间接或直接刺激的神经肌肉制剂进行了补充方案。
多西环素不影响胆碱酯酶活性，也不会对骨骼肌膈肌造成损伤；它作用于兰尼碱受体、肌浆膜和神经元钠通道，导致肌肉烟碱型乙酰胆碱受体的可用性降低，从而产生突触后效应。
除了多西环素的神经元阻断作用外，我们还表明多西环素作用于多个靶点。它被 F55-6（一种神经元 Na+-通道激动剂）和 Ca 拮抗，但不受新斯的明影响。
