Introduction: Zingiber officinale (Zingiberaceae family) is traditionally used in alternative medicine to reduce pain from rheumatoid arthritis and osteoarthritis. Ginger is also often applied for stomach and chest pain, toothaches and as anti-inflammatory agent. The aim of this study is to investigate analgesic and anti-inflammatory activities of Z. officinale dense extract after its transdermal delivery using allyl isothiocyanate (AITC) induced model with further discussion of possible action mechanism of ginger phytoconstituents. Methods: Inflammation was induced by subplantar injection to the plantar fasciitis (aponeurosis) of the hind limb of rats using 30 µL AITC solution (100 µg/limb) in 1,2-propyleneglycol. The dynamics of changes of inflammatory process was evaluated before addition of the inflammation inducer and after 1, 2, 3, 4, 6 and 24 hours of its injection for measuring the volume and the thickness of affected limb. Analgesic activity of ointments with ginger extract was examined using the model of AITC-induced pain. Results: The most effective inhibition of the development of inflammation process was 0.025% ointment with ginger extract, and the highest anti-nociceptive effect was observed at the application of 0.05% ointment 10 minutes before pain inducer agent. Conclusion: Zingiber officinale dense extract was revealed to possess significant antinociceptive and anti-inflammatory actions after its transdermal delivery. Since the pharmacological effects of ginger extract have been investigated on AITC-induced model, we may suggest the vital role of phytoconstituents binding to TRPA1 and TRPV1 ion channels as possible mechanism of action.

Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by ¹H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, respectively. Glycine esters of menthol and borneol exhibited higher antinociceptive action, whereas eugenol derivative significantly suppressed the development of the inflammatory process. The mechanism of competitive binding between terpenoid esters and TRPA1/TRPV1 agonists was proposed explaining significant analgesic effect of synthesized derivatives. For an explanation of high anti-inflammatory activity, competitive inhibition between terpenoid esters and AITC for binding sites of the TRPA1 ion channel has been suggested.

Novel esters of γ-aminobutyric acid (GABA) with monocyclic terpenes were synthesized via Steglich esterification and characterized by ¹H-NMR, IR and mass spectral studies. Their anticonvulsant, analgesic and anti-inflammatory activities were evaluated by a PTZ-induced convulsion model, AITC-induced hyperalgesia and AITC-induced paw edema, respectively. All studied esters, as well as their parent terpenes, were found to produce antinociceptive effects in the AITC-induced model and attenuate acute pain more than the reference drug benzocaine after their topical application. GABA esters of l-menthol and thymol were also shown to exceed the reference drug ibuprofen in their ability to decrease the inflammatory state induced by intraplantar injection of the TRPA1 activator AITC. The present findings indicate that GABA esters of carvacrol and guaiacol are not a classical prodrug and possess their own pharmacological activity. Prolonged antiseizure action of the ester based on the amino acid and guaiacol (200 mg/kg) was revealed at 24 h after oral administration. Furthermore, orally co-administered gidazepam (1 mg/kg) and GABA esters of l-menthol, thymol and carvacrol produce synergistic seizure prevention effects.

Repellent activity of monoterpenoid esters (1-6) with neurotransmitter amino acids (GABA and glycine) was investigated against Aedes aegypti by using a “cloth-patch” assay and compared to reference standard N,N-diethyl-3-methylbenzamide (DEET). Monoterpenoid esters showed repellent activity with minimum effective dosages (MED) in the range of 0.031-0.469 mg/cm². The carvacrol ester of GABA (2, MED of 0.031 ± 0.008 mg/cm²) exhibited the highest repellency of six monoterpenoid esters tested in comparison to the standard repellent DEET (MED of 0.009 ± 0.002 mg/cm²); however, the repellent activity of carvacrol-glycine ester (5) decreased 4-fold compared to the carvacrol-GABA derivative (2). The repellent activities of menthol GABA (1, MED= 0.375 ± 0.000 mg/cm²) and glycine ester (4, MED=0.312 ± 0.063 mg/cm²) were similar The guaiacol-glycine ester (6) was 3.75-fold more efficacious than the guaiacol ester of GABA (3). In the present study, we report repellent efficacy of prolonged exposure to GABA and glycine esters of menthol, carvacrol, guaiacol (1-6) as compared to the repellent activities of their monoterpene moieties alone.

The influence of esters based on gamma-aminobutyric acid (GABA) and mono-/bicyclic terpenoids on membrane structure was investigated. The mechanism of action for terpenoid esters on phospholipids of artificial membranes and lipids isolated from the rat stratum corneum was studied by fluorescence and FT-IR spectroscopy. We report here, that inclusion of monocyclic terpenoid esters in phospholipid liposomes leads to growth of excimer to monomer ratio (I_E/I_M) indicating a decrease of membrane microviscosity. Another mechanism of influence on biomembranes was proposed for ester of bicyclic borneol – in this case a high ratio of vibronic peak intensities (I₁/I₃) was revealed. The addition of terpenoid esters appears in the FT-IR spectra as intensity reduction of absorption bands associated with C = O, P = O and Р–О–С groups of lecithin phospholipids. Similar results were obtained after esters addition to lipids isolated from stratum corneum indicating a decrease of hydrogen bonds number between polar groups of lipids. Thus, the influence of terpenoid esters on molecular organization of the lipid matrix substantiates the feasibility of their use after transdermal delivery in vivo.