Zueva Irina, Lenina Oksana, Kayumova Ramilya, Petrov Konstantin, Masson Patrick
Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center "Kazan Scientific Center of the Russian Academy of Sciences", Arbuzov Str., 8, Kazan, 420088, Russian Federation.
Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center "Kazan Scientific Center of the Russian Academy of Sciences", Arbuzov Str., 8, Kazan, 420088, Russian Federation; Kazan Federal University, Neuropharmacology Laboratory, Kremlevskaya Str 18, Kazan, 480002, Russian Federation.
Chem Biol Interact. 2021 Aug 25;345:109558. doi: 10.1016/j.cbi.2021.109558. Epub 2021 Jun 17.
m-(Tert-butyl) trifluoroacetophenone (TFK), a slow-binding inhibitor of acetylcholinesterase (AChE), a transition state analog of acetylcholine, was investigated as a potential neuroprotectant of central and peripheral AChE against organophosphate paraoxon (POX) toxicity. Acute toxicity and pharmacological effects of TFK were investigated on mice and rats. Intraperitoneal administered TFK has low acute toxicity in mice (LD ≈ 19 mg/kg). Effects on motor function as investigated by rotarod and open field tests showed that TFK up to 5 mg/kg did not alter motor coordination and stereotypical exploration behavior of mice. Passive avoidance test showed that 1 or 5 mg/kg TFK restored memory impairment in scopolamine-induced Alzheimer's disease-like dementia in rats. Pretreatment of mice with 5 mg/kg TFK, 2-3 h before challenge by 2xLD POX provided a modest and short protection against POX toxicity. Futhermore, analysis of POX-induced neuronal degeneration by using fluoro-jade B staining showed that TFK pretreatment, at the dose 5 mg/kg before POX challenge, significantly reduced the density of apoptotic cells in hippocampus and entorhinal cortex of mice. Thus, TFK is capable of reducing POX-induced neurotoxicity.
间-（叔丁基）三氟苯乙酮（TFK）是乙酰胆碱酯酶（AChE）的一种慢结合抑制剂，也是乙酰胆碱的过渡态类似物，被研究作为中枢和外周AChE对抗有机磷酸对氧磷（POX）毒性的潜在神经保护剂。对小鼠和大鼠研究了TFK的急性毒性和药理作用。腹腔注射TFK对小鼠的急性毒性较低（LD≈19mg/kg）。通过转棒试验和旷场试验研究其对运动功能的影响，结果显示，高达5mg/kg的TFK不会改变小鼠的运动协调性和刻板探索行为。被动回避试验表明，1或5mg/kg的TFK可恢复东莨菪碱诱导的大鼠阿尔茨海默病样痴呆的记忆损伤。在2倍LD的POX攻击前2-3小时，用5mg/kg的TFK预处理小鼠，可提供适度且短暂的抗POX毒性保护。此外，通过使用荧光玉髓B染色分析POX诱导的神经元变性，结果显示，在POX攻击前以5mg/kg的剂量进行TFK预处理，可显著降低小鼠海马体和内嗅皮质中凋亡细胞的密度。因此，TFK能够降低POX诱导的神经毒性。
