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S-(+)-Carvone, a Monoterpene with Potential Anti-Neurodegenerative Activity—In Vitro, In Vivo and Ex Vivo Studies

Wojtunik-Kulesza, Karolina A., Rudkowska, Monika, Klimek, Katarzyna, Mołdoch, Jarosław, Agacka-Mołdoch, Monika, Budzyńska, Barbara, Oniszczuk, Anna·2024·Molecules
DOI 10.3390/molecules29184365PMC PMC11434264
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Abstract

Carvone, a natural monoterpene, has been identified in various plants, giving them a characteristic scent. Enantiomers (R-(–) and S-(+)) reveal specific biological activities that are successfully used in traditional medicine for their antifungal, antibacterial, antiparasitic, and anti-influenza properties. The presented paper is based on S-(+)-carvone, characterized by a specific caraway scent, which revealed rich biological activities both in vitro and in vivo. Thus, the aim of the study was to evaluate the potential anti-neurodegenerative activity of S-(+)-carvone, including in vitro experiments (butyrylcholinesterase inhibitory, neuro- and hepatotoxicity as well as neuro- and hepatoprotective activity), in vivo (memory acquisition, locomotor activity), and ex vivo (determination of S-(+)-carvone’s level in tissues collected from mice). Results revealed the multidirectional character of S-(+)-carvone. It has been shown that S-(+)-carvone is capable of butyrylcholinesterase inhibition (40% for 0.025 mg applied onto the plate), and neuroprotection and hepatoprotection at selective concentrations against reactive oxygen species generation and lipid peroxidation along with non-hepatotoxicity character. Additionally, multiple-dose administration of the monoterpene at a dose of 100 mg/kg had a positive influence on memory acquisition. Gas chromatography–mass spectrometry analysis of the plasma and the brain showed that S-(+)-carvone can cross the blood–brain barrier and accumulate in the hippocampus (0.217 µg/mg of tissue), a crucial part of the brain associated with cognition and mental functions.

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Figure 1 Structures of S-(+)-carvone and R-(−)-carvone.
Figure 1 Structures of S-(+)-carvone and R-(−)-carvone.CC BY · PubMed Central
Figure 2 The viability of the SH-SY5Y cell line (human neuroblastoma cells) and the HepG2 cell line (human hepatocellular as well as carcinoma cells) after 48-h incubation with S-(+)-carvone. Galantamine was evaluated as a reference drug. In the case of hepatotoxicity, the results for galantamine were presented in detail in our previous work [13]. Quantitative evaluation of cytotoxicity was assessed using the MTT assay (A,C,E); * Statistically significant differences compared to control cells (incubated without tested compound—marked as Control 0 mM), Student t-test, p < 0.05. Visualization of live (green fluorescence) and dead cells (red fluorescence) after staining with Live/Dead Double kit (B,D,F); magnification 100×, scale bar = 150 μM.
Figure 2 The viability of the SH-SY5Y cell line (human neuroblastoma cells) and the HepG2 cell line (human hepatocellular as well as carcinoma cells) after 48-h incubation with S-(+)-carvone. Galantamine was evaluated as a reference drug. In the case of hepatotoxicity, the results for galantamine were presented in detail in our previous work [13]. Quantitative evaluation of cytotoxicity was assessed using the MTT assay (A,C,E); * Statistically significant differences compared to control cells (incubated without tested compound—marked as Control 0 mM), Student t-test, p < 0.05. Visualization of live (green fluorescence) and dead cells (red fluorescence) after staining with Live/Dead Double kit (B,D,F); magnification 100×, scale bar = 150 μM.CC BY · PubMed Central
Figure 3 The CLSM images demonstrate the neuroprotective and hepatoprotective activity of S-(+)-carvone after induction of oxidative stress and lipid peroxidation. Additionally, galantamine was used as a reference drug. Cells were stained with Hoechst 33342 for nuclei visualization (blue fluorescence) and with CellROXTM Deep Red Reagent for visualization of oxidative stress (red fluorescence) or with Image-ITTM Lipid Peroxidation for visualization of lipid peroxidation (green fluorescence) or lack of lipid peroxidation (red fluorescence); magnification 200×, scale bar = 70 μm.
Figure 3 The CLSM images demonstrate the neuroprotective and hepatoprotective activity of S-(+)-carvone after induction of oxidative stress and lipid peroxidation. Additionally, galantamine was used as a reference drug. Cells were stained with Hoechst 33342 for nuclei visualization (blue fluorescence) and with CellROXTM Deep Red Reagent for visualization of oxidative stress (red fluorescence) or with Image-ITTM Lipid Peroxidation for visualization of lipid peroxidation (green fluorescence) or lack of lipid peroxidation (red fluorescence); magnification 200×, scale bar = 70 μm.CC BY · PubMed Central
Figure 4 The effect of single-dose administration of S-(+)-carvone (CV) on memory acquisition processes in the PA test in mice. CV (50 or 100 mg/kg i.p.) or saline solution (i.p.) were administered 30 min before training. Subsequently, 24 h after training, the animals were re-tested. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 10. The statistical analysis of the data was performed using a one-way analysis of variance (ANOVA) followed by the post hoc Dunnett’s test.
Figure 4 The effect of single-dose administration of S-(+)-carvone (CV) on memory acquisition processes in the PA test in mice. CV (50 or 100 mg/kg i.p.) or saline solution (i.p.) were administered 30 min before training. Subsequently, 24 h after training, the animals were re-tested. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 10. The statistical analysis of the data was performed using a one-way analysis of variance (ANOVA) followed by the post hoc Dunnett’s test.CC BY · PubMed Central
Figure 5 The effect of multiple-dose administration of S-(+)-carvone (CV) on the memory acquisition processes in the PA test in mice. CV (50 and 100 mg/kg, i.p.) or saline solution (i.p.) were administered for 6 days, twice daily. On the seventh day, the appropriate group of mice received CV (50 or 100 mg/kg, i.p.) or saline solution (i.p.) 30 min before training. Subsequently, 24 h after training, the animals were re-tested. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 9–10. The statistical analysis of the data was performed using a one-way analysis of variance (ANOVA) followed by the post hoc Dunnett’s test. ** p < 0.01 vs. saline-treated control group.
Figure 5 The effect of multiple-dose administration of S-(+)-carvone (CV) on the memory acquisition processes in the PA test in mice. CV (50 and 100 mg/kg, i.p.) or saline solution (i.p.) were administered for 6 days, twice daily. On the seventh day, the appropriate group of mice received CV (50 or 100 mg/kg, i.p.) or saline solution (i.p.) 30 min before training. Subsequently, 24 h after training, the animals were re-tested. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 9–10. The statistical analysis of the data was performed using a one-way analysis of variance (ANOVA) followed by the post hoc Dunnett’s test. ** p < 0.01 vs. saline-treated control group.CC BY · PubMed Central
Figure 6 The effect of single-dose S-(+)-carvone (CV) administration on memory acquisition processes is impaired by a single-dose injection of scopolamine in the PA test. CV (50 or 100 mg/kg, i.p.), saline solution (i.p.), or scopolamine (1 mg/kg, s.c.) were administered 30 min before training. Subsequently, 24 h after training, the animals were re-tested again. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 8–10. The statistical analysis of the data was performed using a two-way analysis of variance (ANOVA) followed by the post hoc Bonferroni’s test. * p < 0.05; ** p < 0.01 vs. saline-treated control group; #### p < 0.0001 vs. CV 100 mg/kg.
Figure 6 The effect of single-dose S-(+)-carvone (CV) administration on memory acquisition processes is impaired by a single-dose injection of scopolamine in the PA test. CV (50 or 100 mg/kg, i.p.), saline solution (i.p.), or scopolamine (1 mg/kg, s.c.) were administered 30 min before training. Subsequently, 24 h after training, the animals were re-tested again. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 8–10. The statistical analysis of the data was performed using a two-way analysis of variance (ANOVA) followed by the post hoc Bonferroni’s test. * p < 0.05; ** p < 0.01 vs. saline-treated control group; #### p < 0.0001 vs. CV 100 mg/kg.CC BY · PubMed Central
Figure 7 The effect of multiple-dose S-(+)-carvone (CV) administration on memory acquisition processes is impaired by a single-dose injection of scopolamine in the PA test. CV (50 or 100 mg/kg, i.p.) or saline solution (i.p.) was administered for 6 days, twice daily. On the seventh day, the appropriate group of mice received CV (50 or 100 mg/kg, i.p.) or saline solution (i.p.) or scopolamine (1 mg/kg, s.c.) 30 min before training. The animals were tested again 24 h after training. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 9–10. The statistical analysis of the data was performed using a two-way analysis of variance (ANOVA) followed by the post hoc Bonferroni’s test. * p < 0.05; *** p < 0.001 vs. saline-treated control group; #### p < 0.0001 vs. CV 100 mg/kg.
Figure 7 The effect of multiple-dose S-(+)-carvone (CV) administration on memory acquisition processes is impaired by a single-dose injection of scopolamine in the PA test. CV (50 or 100 mg/kg, i.p.) or saline solution (i.p.) was administered for 6 days, twice daily. On the seventh day, the appropriate group of mice received CV (50 or 100 mg/kg, i.p.) or saline solution (i.p.) or scopolamine (1 mg/kg, s.c.) 30 min before training. The animals were tested again 24 h after training. The results were expressed as a latency index (IL) and presented as a mean ± SEM, n = 9–10. The statistical analysis of the data was performed using a two-way analysis of variance (ANOVA) followed by the post hoc Bonferroni’s test. * p < 0.05; *** p < 0.001 vs. saline-treated control group; #### p < 0.0001 vs. CV 100 mg/kg.CC BY · PubMed Central

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Metadata

Authors
Wojtunik-Kulesza, K. A., Rudkowska, M., Klimek, K., Mołdoch, J., Agacka-Mołdoch, M., Budzyńska, B., & Oniszczuk, A.
Venue
Molecules
Publisher
MDPI AG
Published
2024-09-13
Volume
29
Issue
18
Pages
4365
ISSN
1420-3049
DOI
10.3390/molecules29184365
PMC
PMC11434264
Cited by
19
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Medical University of Lublin (PBmb65)

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Wojtunik-Kulesza, K. A., Rudkowska, M., Klimek, K., Mołdoch, J., Agacka-Mołdoch, M., Budzyńska, B., & Oniszczuk, A. (2024). S-(+)-Carvone, a Monoterpene with Potential Anti-Neurodegenerative Activity—In Vitro, In Vivo and Ex Vivo Studies. Molecules. https://doi.org/10.3390/molecules29184365

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