Almeida Antonia Amanda Cardoso de, Ferreira José Roberto de Oliveira, de Carvalho Rusbene Bruno Fonseca, Rizzo Marcia Dos Santos, Lopes Luciano da Silva, Dittz Dalton, Castro E Souza João Marcelo de, Ferreira Paulo Michel Pinheiro
Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, 64049-550, Brazil.
Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Universitária Avenue, Ininga, Teresina, Piauí, 64049-550, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Dec;393(12):2301-2314. doi: 10.1007/s00210-020-01943-w. Epub 2020 Jul 11.
The compound (+)-limonene epoxide has antioxidant, anxiolytic, and antihelminthic properties. However, investigations to determine its long-term exposure were not performed. We investigated the systemic toxicological profile after chronic exposure as well as the antidepressant and antiepileptic potentialities of (+)-limonene epoxide on mice. Initially, we evaluated acute toxicity on Artemia salina nauplii and cytotoxicity on mice erythrocytes and peripheral blood mononuclear cells (PBMC). Aftterwards, mice were chronically treated for 120 days by gavage with (+)-limonene epoxide (25, 50, and 75 mg/kg/day) and this exposure was assessed by pathophysiological measurements. For antidepressant and anticonvulsivant analysis, we performed the forced swimming and tail suspension protocols and pentylenetetrazol- and picrotoxin-induced seizures, respectively. (+)-Limonene epoxide showed a LC value of 318.7 μg/mL on A. salina shrimps, caused lysis of red blood cells at higher concentrations only but did not show cytotoxicity on PMBC, which suggests pharmacological safety if plasma concentrations do not exceed 100 μg/mL. Macroscopic, hematological, clinical chemistry, and nutritional changes were not detected, though focal areas of hepatic necrosis, inflammatory infiltrate, and karyolysis have been detected at 75 mg/kg/day. The compound inhibited the developing of pentylenetetrazol- and picrotoxin-induced seizures, decreased deaths, and reduced immobility times, mainly at 75 mg/kg. So, it reversed reserpine effects, suggesting antidepressant effects should be linked to serotonergic and/or adrenergic transmission. It is feasible that (+)-limonene epoxide plays a benzodiazepine-like anticonvulsive action and may be also recommended as an antidote for poisonings caused by central depressants.
化合物（+）-柠檬烯环氧化物具有抗氧化、抗焦虑和抗蠕虫特性。然而，尚未进行确定其长期暴露情况的研究。我们研究了（+）-柠檬烯环氧化物对小鼠慢性暴露后的全身毒理学特征以及其抗抑郁和抗癫痫潜力。最初，我们评估了其对卤虫无节幼体的急性毒性以及对小鼠红细胞和外周血单核细胞（PBMC）的细胞毒性。之后，通过灌胃对小鼠进行为期120天的（+）-柠檬烯环氧化物慢性治疗（剂量为25、50和75毫克/千克/天），并通过病理生理学测量评估这种暴露情况。对于抗抑郁和抗惊厥分析，我们分别进行了强迫游泳和悬尾实验以及戊四氮和印防己毒素诱发的癫痫实验。（+）-柠檬烯环氧化物对卤虫的LC值为318.7微克/毫升，仅在较高浓度下导致红细胞裂解，但对PBMC未显示细胞毒性，这表明如果血浆浓度不超过100微克/毫升，则具有药理学安全性。尽管在75毫克/千克/天的剂量下检测到肝坏死灶、炎症浸润和核溶解，但未检测到宏观、血液学、临床化学和营养方面的变化。该化合物抑制了戊四氮和印防己毒素诱发的癫痫发作的发展，减少了死亡，并缩短了不动时间，主要在75毫克/千克时。因此，它逆转了利血平的作用，表明抗抑郁作用可能与5-羟色胺能和/或肾上腺素能传递有关。（+）-柠檬烯环氧化物发挥类似苯二氮䓬类的抗惊厥作用是可行的，也可能被推荐作为中枢抑制剂中毒的解毒剂。
