Research Laboratory in Biochemical Pharmacology (LaFarBio), Neurobiotechnology Research Group (GPN), Center for Chemical, Pharmaceutical and Food Sciences, Federal University of Pelotas (UFPel), Campus Capão do Leão, Pelotas, RS, CEP 96010-900, Brazil.
Laboratory of Organic Catalysis and Biocatalysis, Federal University of Grande Dourados, Dourados, MS, Brazil.
Psychopharmacology (Berl). 2024 Nov;241(11):2385-2402. doi: 10.1007/s00213-024-06647-0. Epub 2024 Jul 15.
The compound 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) has recently been shown to inhibit in vitro acetylcholinesterase activity, reduce cognitive damage, and improve neuropsychic behavior in mice, making it a promising molecule to treat depression.
This study investigated the antidepressant-like action of MTDZ in mice and its potential mechanisms of action.
Molecular docking assays were performed and suggested a potential inhibition of monoamine oxidase A (MAO-A) by MTDZ. The toxicity study revealed that MTDZ displayed no signs of toxicity, changes in oxidative parameters, or alterations to biochemistry markers, even at a high dose of 300 mg/kg. In behavioral tests, MTDZ administration reduced immobility behavior during the forced swim test (FST) without adjusting the climbing parameter, suggesting it has an antidepressant effect. The antidepressant-like action of MTDZ was negated with the administration of 5-HT1A, 5-HT1A/1B, and 5-HT3 receptor antagonists, implying the involvement of serotonergic pathways. Moreover, the antidepressant-like action of MTDZ was linked to the NO system, as L-arginine pretreatment inhibited its activity. The ex vivo assays indicated that MTDZ normalized ATPase activity, potentially linking this behavior to its antidepressant-like action. MTDZ treatment restricted MAO-A activity in the cerebral cortices and hippocampi of mice, proposing a selective inhibition of MAO-A associated with the antidepressant-like effect of the compound.
These findings suggest that MTDZ may serve as a promising antidepressant agent due to its selective inhibition of MAO-A and the involvement of serotonergic and NO pathways.
最近的研究表明，化合物 5-((4-甲氧基苯基)硫代)苯并[c][1,2,5]噻二唑（MTDZ）可以抑制体外乙酰胆碱酯酶活性，减少认知损伤，并改善小鼠的神经精神行为，使其成为治疗抑郁症的有前途的分子。
本研究探讨了 MTDZ 在小鼠中的抗抑郁样作用及其潜在的作用机制。
进行了分子对接实验，结果表明 MTDZ 可能抑制单胺氧化酶 A（MAO-A）。毒性研究表明，即使在 300mg/kg 的高剂量下，MTDZ 也没有显示出毒性、氧化参数变化或生物化学标志物改变的迹象。在行为测试中，MTDZ 给药减少了强迫游泳试验（FST）中的不动行为，而不调整攀爬参数，表明它具有抗抑郁作用。5-HT1A、5-HT1A/1B 和 5-HT3 受体拮抗剂的给药否定了 MTDZ 的抗抑郁样作用，表明其涉及 5-羟色胺能途径。此外，MTDZ 的抗抑郁样作用与 NO 系统有关，因为 L-精氨酸预处理抑制了其活性。离体实验表明，MTDZ 使 ATP 酶活性正常化，这可能将这种行为与其抗抑郁样作用联系起来。MTDZ 治疗限制了小鼠大脑皮质和海马中的 MAO-A 活性，提示该化合物的抗抑郁样作用与 MAO-A 的选择性抑制有关。
这些发现表明，MTDZ 可能成为一种有前途的抗抑郁药物，因为它选择性地抑制 MAO-A，并且涉及 5-羟色胺能和 NO 途径。
