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

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...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-1298 1432-1912 1432-1912
DOI:	10.1007/s00210-024-03173-w