Non-clinical investigations about cytotoxic and anti-platelet activities of gamma-terpinene

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 397; no. 10; pp. 8145 - 8160
• Main Authors: Souza, Railson Pereira, Pimentel, Vinícius Duarte, de Sousa, Rayran Walter Ramos, Sena, Emerson Portela, da Silva, Alda Cássia Alves, Dittz, Dalton, Ferreira, Paulo Michel Pinheiro, de Oliveira, Aldeídia Pereira
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2024; Springer Nature B.V
• Subjects: Affinity; Animals; Bioavailability; Biomedical and Life Sciences; Biomedicine; Blood Platelets - drug effects; Blood Platelets - metabolism; Cardiovascular system; Cell Line; Cell Survival - drug effects; Cyclohexane; Cyclohexane Monoterpenes - pharmacology; Cytotoxicity; Essential oils; Eucalyptus; Hemostasis; Male; Melaleuca alternifolia; Mice; Molecular Docking Simulation; Monoterpenes - pharmacology; Neurosciences; Origanum vulgare; Oxidative stress; Pharmacokinetics; Pharmacology/Toxicology; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Purine receptors; Rats; Rats, Inbred SHR; Rats, Wistar; Rosmarinus officinalis; Terpinene; Therapeutic targets; Thromboembolism; Thymus vulgaris; Cyclohexane monoterpenes; Purine receptors; Toxicity; Molecular docking
• ISSN: 0028-1298; 1432-1912; 1432-1912
• DOI: 10.1007/s00210-024-03173-w

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
50
= 333.3 µM) and SVEC 4-10 (CC
50
= 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.