A.E.Arbusov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Kazan, Russia.
Br J Pharmacol. 2011 Jun;163(4):732-44. doi: 10.1111/j.1476-5381.2011.01211.x.
The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain.
Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated.
The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL.
Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools.
新型乙酰胆碱酯酶（AChE）抑制剂 6-甲基尿嘧啶烷基铵衍生物（ADEMS）对呼吸肌膈肌的敏感性明显低于运动肌趾长伸肌（EDL）。本研究评估了膈肌与四肢肌肉之间以及肌肉与大脑之间敏感性不同的几种可能原因。
使用微终板电流幅度增加和衰减时间延长来评估肌肉中的抗胆碱酯酶活性。在海马切片中，同步网络活动的诱导用于跟踪胆碱酯酶抑制。还估计了来自 EDL 和大脑的纯化 AChE 的抑制剂敏感性。
ADEMS 敏感性的肌肉间差异部分由膈肌中更高水平的 mRNA 和 1,3-双[5（二乙基-o-硝基苄基铵）戊基]-6-甲基尿嘧啶二溴化物（C-547）-抗性 BuChE 的活性解释。此外，膈肌 AChE 对 C-547 的敏感性比 EDL 低 20 多倍。跑步机运动增加了 PRiMA AChE(G4)的数量，大大降低了 EDL 对 C-547 的敏感性，但 ColQ AChE(A12)分子形式没有变化。肌肉中存在的 A12 形式似乎对 C-547 更敏感。大脑中主要的 AChE 形式 PRiMA AChE(G4)显然不太敏感，因为大脑胆碱酯酶活性对 C-547 的抵抗力比 EDL 高三个数量级。
我们的发现表明，ADEMS 化合物可用于选择性抑制 AChE 并作为潜在的治疗工具。
