Postgraduate Program in Pharmacology, Center for Research on Medicinal Plants (NPPM), Federal University of Piauí, Teresina, 64049-550, Brazil.
Laboratory of Cardiovascular Pharmacology (Lafac), Federal University of Piauí, Teresina, 64049-550, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct;397(10):8145-8160. doi: 10.1007/s00210-024-03173-w. Epub 2024 May 27.
Gamma-terpinene (γ-TPN) is a cyclohexane monoterpene isolated from plant essential oils, such as tea tree (Melaleuca alternifolia), oregano (Origanum vulgare), rosemary (Rosmarinus officinalis L.), thyme (Thymus vulgaris Marchand), and eucalyptus (Eucalyptus sp.). Terpenes are widely studied molecules pharmacologically active on the cardiovascular system, hemostasis, and antioxidant actions. Herein, it was investigated the cytotoxic and antiplatelet activity of γ-TPN using different non-clinical laboratory models. For in silico evaluation, the PreADMET, SwissADME, and SwissTargetPrediction softwares were used. Molecular docking was performed using the AutoDockVina and BIOVIA Discovery Studio databases. The cytotoxicity of γ-TPN was analyzed by the MTT assay upon normal murine endothelial SVEC4-10 and fibroblast L-929 cells. Platelet aggregation was evaluated with platelet-rich (PRP) and platelet-poor (PPP) plasma from spontaneously hypertensive rats (SHR), in addition to SVEC4-10 cells pre-incubated with γ-TPN (50, 100, and 200 µM) for 24 h. SHR animals were pre-treated by gavage with γ-TPN for 7 days and divided into four groups (negative control, 25, 50, and 100 mg/kg). Blood samples were collected to measure nitrite using the Griess reagent. Gamma-TPN proved to be quite lipid-soluble (Log P = +4.50), with a qualified profile of similarity to the drug, good bioavailability, and adequate pharmacokinetics. It exhibited affinity mainly for the P2Y12 receptor (6.450 ± 0.232 Kcal/mol), moderate cytotoxicity for L-929 (CC = 333.3 µM) and SVEC 4-10 (CC = 366.7 µM) cells. The presence of γ-TPN in SVEC 4-10 cells was also able to reduce platelet aggregation by 51.57 and 44.20% at lower concentrations (50 and 100 µM, respectively). Then, γ-TPN has good affinity with purinergic receptors and an effect on the reversal of platelet aggregation and oxidative stress, being promising and safe for therapeutic targets and subsequent studies on the control of thromboembolic diseases.
γ-松油烯（γ-TPN）是一种从植物精油中分离出来的环己烷单萜，如茶树（桃金娘科）、牛至（牛至属）、迷迭香（迷迭香）、百里香（百里香）和桉树（桉树属）。萜类化合物是广泛研究的具有心血管系统、止血和抗氧化作用的药理学活性的分子。在此，使用不同的非临床实验室模型研究了 γ-TPN 的细胞毒性和抗血小板活性。对于计算机评估，使用了 PreADMET、SwissADME 和 SwissTargetPrediction 软件。使用 AutoDockVina 和 BIOVIA Discovery Studio 数据库进行分子对接。通过 MTT 测定法分析 γ-TPN 在正常鼠内皮 SVEC4-10 和成纤维细胞 L-929 细胞中的细胞毒性。通过富含血小板（PRP）和血小板（PPP）的血浆从自发性高血压大鼠（SHR）评估血小板聚集，此外，SVEC4-10 细胞用 γ-TPN（50、100 和 200 µM）孵育 24 小时。SHR 动物用 γ-TPN 灌胃预处理 7 天，并分为 4 组（阴性对照、25、50 和 100 mg/kg）。收集血液样本，用 Griess 试剂测量亚硝酸盐。γ-TPN 证明具有相当的脂溶性（Log P = +4.50），具有与药物相似的合格特征、良好的生物利用度和足够的药代动力学。它主要表现出对 P2Y12 受体的亲和力（6.450 ± 0.232 Kcal/mol），对 L-929（CC = 333.3 µM）和 SVEC 4-10（CC = 366.7 µM）细胞具有中度细胞毒性。γ-TPN 存在于 SVEC 4-10 细胞中，也能以较低浓度（分别为 50 和 100 µM）降低血小板聚集 51.57%和 44.20%。然后，γ-TPN 与嘌呤能受体具有良好的亲和力，并对血小板聚集和氧化应激的逆转具有作用，具有治疗靶点的潜力，并且在随后的血栓栓塞性疾病控制研究中是安全的。
