Ameliorative role of β-Caryophyllene on antioxidant biomarkers in Paroxetine induced erectile dysfunctional rats

doi:10.21203/rs.3.rs-3931958/v1

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Ameliorative role of β-Caryophyllene on antioxidant biomarkers in Paroxetine induced erectile dysfunctional rats

https://doi.org/10.21203/rs.3.rs-3931958/v1

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Erectile dysfunction is a leading cause of male infertility linked to oxidative stress. This study aimed to assess B-Caryophyllene (BCP) as an antioxidant on penile tissue in Paroxetine-induced rats. In vitro tests evaluated BCP's antioxidant properties, including ferric reduction, DPPH, ABTS, and hydroxyl radical scavenging, plus TBARs assays. Forty-five rats were divided into nine groups: Normal control (NC), BCP (10 mg/kg), BCP (20 mg/kg), Sildenafil citrate (SC) (20mg/kg), BCP + SC (20 mg/kg), Paroxetine (PD) (20 mg/kg), PD + BCP (10mg/kg), PD + BCP (20mg/kg), and PD + SC (20 mg/kg). PD was orally administered for seven days. BCP and SC treatments occurred from day 8 to 14. Enzyme activities (S.O.D., Catalase, G.S.T., and GPx) and TBARS were measured spectrophotometrically. PD caused erectile dysfunction, reducing mount latency (ML) and intromission latency (I.L.). BCP concentration-dependently enhanced reducing power, ABTS, OH scavenging, and % DPPH inhibition, significantly lowering %TBARS compared to sildenafil citrate. IC50 values for OH radical, DPPH, and Iron (II) ion chelation were 10.98 µg/mL, 59.14 µg/mL, and 17.36 µg/mL. In vivo, BCP significantly (p < 0.001) increased S.O.D., Catalase, and GPx activities. G.S.T. activity significantly (p < 0.01) increased with BCP (20 mg/kg). BCP (20 mg/kg) significantly (p < 0.001) lowered TBARS more effectively than SC. BCP, especially at 20 mg/kg, displayed potent antioxidative effects on penile tissue in Paroxetine-induced rats.

Toxicology

Applied Biochemistry

β-caryophyllene

Sildenafil citrate

Paroxetine

Oxidative stress

Erectile dysfunction

Erectile dysfunction (ED) is characterized by the persistent inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance (Sooriyamoorthy & Leslie, 2023). This condition is considered common and exhibits an increased prevalence with advancing age (Jackson et al., 2010; Oyelade et al., 2016; Rew & Heidelbaugh, 2016).

β-Caryophyllene (β-CBP) is a naturally occurring bicyclic lipophilic sesquiterpene lactone compound (Chang et al., 2013). It is abundantly found in essential oils and is a constituent of various dietary and edible plants, including cloves, cinnamon, rosemary, hops, and black pepper (Di Sotto et al., 2013). Notably, it contributes to the pungency of black pepper (Horváth et al., 2012), and has served as a flavoring agent since the 1930s (Calleja et al., 2013).

β-CBP exhibits diverse biological activities, including antioxidant, anti-inflammatory, antibiotic, anticarcinogenic, and local anaesthetic properties (Calleja et al., 2013; Gushiken et al., 2022). Additionally, it demonstrates anxiolytic-like effects (da Silva Oliveira et al., 2021) and serves as a potent neuroprotective agent, with its neuroprotection partially attributed to the modulation of inflammatory mediators (Chang et al., 2013). Recent studies have indicated its efficacy in the treatment of endometriosis (Abbas et al., 2013) and its cytotoxic effects on a broad spectrum of tumor cell lines Amiel et al., 2012).

However, limited information is available concerning the potential erectogenic effects of β-CBP. Therefore, this study aims to evaluate the impact of β-Caryophyllene on key enzymes relevant to erectile dysfunction in rats.

3.1 Materials

3.1.1 Chemicals and Reagents

Chemicals and reagents that were used included acetylcholine iodide, gallic acid, and Folin-Cioacalteau reagent obtained from Sigma-Aldrich (St. Louis, MO, USA). β-caryophyllene (purity C98.5%), metronidazole, tween 80, and DurcupanTM ACM Fulka embedding mixture from Sigma-Aldrich, USA. Thiobarbituric acid (TBA), trichloroacetic acid (TCA), quercetin, 1,1-diphenyl-2-picrylhydrazyl (DPPH), and 2-deoxyribose were procured from Sigma-Aldrich Chemie (USA). Sodium carbonate, ferric chloride, aluminium chloride, potassium acetate, potassium ferricyanide, tris salt, ferric sulfate, as well as other reagents used were of analytical grade; glass-distilled water was also used.

Methodology

Determination of DPPH radical scavenging ability

The radical scavenging ability of the sample against DPPH free radical is to be evaluated as described by Gyamfil et al. (1999).

Determination of Fe (II) chelating ability

The method of Puntel et al. (2005) will be used to determine the iron chelating ability of the samples.

Determination of ferric reducing antioxidant property

The reducing property of the samples was determined by assessing the ability of the samples to reduce FeCl₃ solution as described by Oyiazu (1986).

Total antioxidant capacity

The total antioxidant capacity of the sample will be determined against 2, 2’- azino-bis (ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical according to the method described by Re et al.(1999).

Inhibition of Fenton reaction (degradation of deoxyribose)

The method of Halliwell and Gutteridge (1981) will be used to determine the ability of the samples to prevent Fe²⁺/H₂O₂induced decomposition of deoxyribose.

Experimental Animal handling and Feeding

Wistar male and female rats weighing 200-220g were used in this study. The animals were obtained from the Federal University of Technology, Akure, Nigeria. The animals were handled according to the guidelines of the National Council for Animal Experiments Control (CONCEA) and in accordance with the International Guiding Principles for Biomedical Research Involving Animals. The male and female rats were given normal feed.

After two weeks of acclimatization, the rats were randomly divided into eight (8) groups of six (6) animals each and fed for fourteen (14) days with free access to feed and water. The handling of the animals was carried out in accordance with the recommended international standards.

The selected dose was 10 mg/kg/day, chosen based on previous studies (Chang et al., 2013; Horváth et al., 2012; Abbas et al., 2013).

Experimental design

Group I Normal Control rats – were administered the vehicle (1% ethanol)

Group II β-caryophyllene (10 mg/kg)

Group III β-caryophyllene (20 mg/kg)

Group IV Sildenafil citrate (20 mg/kg/day)

Group V β-caryophyllene (20 mg/kg/day) + sildenafil citrate (20 mg/kg/day)

Group VI Paroxetine Induced Erectile Dysfunction (PIED) rat

Group VII Paroxetine Induced Erectile Dysfunction + β-caryophyllene (10 mg/kg)

Group VIII Paroxetine Induced Erectile Dysfunction + (20 mg/kg) of β-caryophyllene

Group IX Paroxetine Induced Erectile Dysfunction + Sildenafil citrate (20 mg/kg/day)

At the end of the 14th day, the rats were subjected to sexual (male paired with female) behavioural assays according to Thawatchai et al. (2012).

Sexual Behaviour

The sexual behavioural assay was carried out according to a modified method of Thawatchai et al. (2012).

Determination of penile superoxide dismutase (SOD) activity

Superoxide dismutase (SOD) activity was determined by the method of Mistra & Fridovich (1972).

Determination of penile catalase activity

This is carried out according to the modified method of Clairborne (1985).

Determination of penile reduced glutathione (GSH) level

Reduced glutathione (GSH) level was determined by the method of Jollow et al. (1974).

Determination of penile glutathione-S-transferase (GST) activity

This was carried out according to the method of Mannervik and Guthenberg (1981).

Data Analysis

The results were expressed as the means ± SEM. Statistical significance will be determined by two-way ANOVA followed by a post-hoc Tukey test for multiple comparisons using Prism software (GraphPad, version 6.0, Carlsbad, CA).

In vitro antioxidant potentials of β-Caryophyllene

The ferric reducing antioxidant properties (FRAP) analysis of β-CBP yielded results indicating comparatively lower reducing potentials in contrast to Sildenafil Citrate, as depicted in Fig. 1a. Likewise, the ABTS radical scavenging capacity of β-CBP is illustrated as trolox equivalent antioxidant capacity in Fig. 1b, revealing the highest ABTS radical scavenging ability.

The OH radical scavenging capability of β-CBP, presented in Fig. 1c along with associated IC50 values in Table 1, demonstrates a concentration-dependent scavenging of OH radicals. Furthermore, lipid peroxidation, as displayed in Fig. 1d, exhibited a significant increase in the percentage of TBARS produced upon the addition of pro-oxidants. Conversely, a concentration-dependent reduction in the % TBARS produced was observed upon the inclusion of β-CBP.

Figure 1e showcases the DPPH radical scavenging capacity of β-CBP, while Table 1 details the corresponding IC50 values. This presentation highlights the concentration-dependent scavenging of DPPH radicals. In addition, Fig. 1f illustrates the iron chelating ability of β-CBP, where results indicate a concentration-dependent chelation of Fe²⁺. The IC50 values in Table 1 provide insight into the chelating potential of β-CBP.

Figure 1. invitro antioxidant activity of β-Caryophyllene a. Ferric Reducing Antioxidant scavenging ability, b. ABTS radical scavenging ability of β-Caryophyllene, c. OH radical scavenging ability, d. % TBARS, e. DPPH radical scavenging ability, f. Iron chelation scavenging ability

BCP: β-Caryophyllene; Values represent mean ± standard deviation of triplicate readings.

Table 1

IC₅₀ values of DPPH, Fe²⁺ chelation and OH radical of β-Caryophyllene
	IC₅₀ (µg/mL)
Sample	DPPH	Fe²⁺ Chelation	OH radical
β-Caryophyllene	59.14	17.36	10.98

Values represent mean ± standard deviation of replicate readings.

Effects of β-Caryophyllene on antioxidant enzymes

Figure 2a illustrates the activity of superoxide dismutase (SOD) within liver tissue. The results highlight a significant variance (p < 0.05) between the PD group and the control group. Additionally, all other groups exhibited increased SOD activity, significantly differing (p < 0.05) from both the control and PD groups. Notably, the β-CBP groups displayed a further increase compared to the control and PD groups.

In Fig. 2b, the impact of β-CBP on catalase activity in liver tissue is presented. The results reveal a significant rise in catalase activity in the PD group compared to the control group (p < 0.05). All remaining groups also showed marked differences (p < 0.05) when compared to the control and PD groups.

Moving on to Fig. 2c, the influence of β-CBP on GST activity in liver tissue is depicted. The data illustrates an increase in GST activity in the PD group, signifying a significant distinction (p < 0.05) from the control group. Furthermore, all groups displayed notable variances (p < 0.05) when compared with the normal control and PD groups.

Figure 2d demonstrates the effect of β-CBP on glutathione peroxidase (GPx) in liver tissue. The results exhibit a significant elevation in GPx activity in the PD group (p < 0.05), and all other groups displayed marked differences (p < 0.05) in comparison to the normal control and PD groups.

Figure 2e portrays the effects of β-CBP on lipid peroxidation within liver homogenate. β-CBP effectively reduced lipid peroxidation activity in comparison to the PD group. These findings indicate significant distinctions (p < 0.05) among all groups, with the PD groups treated with β-CBP displaying a noteworthy difference (p < 0.05) compared to the control groups.

Figure 2

Effect of β-Caryophyllene on antioxidant liver biomarkers of paroxetine-induced rats; a. SOD activity, b. catalase activity, c. glutathione-S-transferase (GST) activity, d. glutathione peroxidase (GPx) activity, e. Lipid Peroxidation activity. Values represent means ± standard deviation of replicate readings (n = 8). Values with the same alphabet along the same column are not significantly different (p < 0.05). ‘⁎’, ‘⁎⁎’, ‘⁎⁎⁎‘means significantly different from control group at p < 0.05, p < 0.01, p < 0.001 respectively. ‘ᴧ’, ‘ᴧᴧ’, ‘ᴧᴧᴧ’ means significantly different from PD-treated group at p < 0.05, p < 0.05, p < 0.01, p < 0.001 respectively.

Previous research has established a link between antidepressant therapies, notably paroxetine treatment, and sexual dysfunction (Jing & Straw-Wilson, 2016; AlBreiki et al., 2020). In men, sexual dysfunction has been associated with erectile impairment and oxidative degradation of penile tissues (Sheweita et al., 2015; Adefegha et al., 2020). Notably, phenolic compounds have been recognized for their ability to alleviate pathological pathways in erectile dysfunction (ED) (Oboh et al., 2015).

Oxidative stress has been identified as a contributing factor in the development of ED (Agarwal et al., 2006). Biomarkers of oxidative stress have been detected in cavernosal tissues of ED patients (Sheweita et al., 2015). Another mechanism involves the inhibition of lipid peroxidation, wherein flavonoids chelate metal ions, preventing Fe²⁺-induced lipid peroxidation in penile tissues (Boadi et al., 2021). A reduction in non-protein thiols within penile tissues, as observed in this study, suggests a compromised antioxidant defense mechanism, rendering penile tissues susceptible to oxidative damage and potential impairment of erectile function. It is worth noting that the antioxidant defense system plays a pivotal role in shielding cells and tissues from oxidative harm (Ponnampalam et al., 2022).

Empirical evidence has demonstrated that an imbalance between free radical generation and antioxidant defense capacity in the testes and epididymis of rats may signify sexual dysfunction (Aitken & Roman, 2008; Finelli et al., 2022; Kaltsas, 2023). Reactive oxygen species, particularly superoxides, play a central role in the impairment of erectile function within cavernosal tissues (Agarwal et al., 2006). Consequently, therapeutic interventions involving antioxidant therapy aimed at bolstering the antioxidant defense system may prove effective in ED treatment or prevention. In this study, we observed that the administration of β-CBP increased non-protein thiol levels in penile tissues of both normal and PD-induced rats. The DPPH scavenging free radical operates by transferring hydrogen atoms (Gulcin and Alwasel, 2023). Recent research suggests that phenolic compounds exert their antioxidant potential through the donation of hydrogen atoms to reactive oxygen species (Kruk et al., 2022; Kumar & Goel, 2019). Monitoring the decrease in the radical in terms of declining absorbance values facilitates the assessment of the antioxidant activity of the product. β-CBP efficiently reduced and decolorized 1,1-diphenyl-2-picrylhydrazyl (DPPH) at low concentrations by donating hydrogen atoms (Fig. 1e). This electron transfer-based assay evaluates an antioxidant's capacity to reduce an oxidant. The degree of color change corresponds with the sample's antioxidant activity (Sen Gupta & Ghosh, 2013). However, at higher concentrations, potential color interference by β-CBP may result in a lower measured DPPH activity (Miguel, 2010; Al Jumayi, 2022), as evident in the results and IC50 value (Fig. 1e and Table 1). The bivalent transition metal ion Fe²⁺ is a potent inducer of lipid (Repetto et al., 2010). It accelerates lipid oxidation by breaking down hydrogen and lipid peroxides into reactive free radicals (Martemucci et al., 2022). The results obtained in our study demonstrate that β-CBP chelated Fe²⁺ in a concentration-dependent manner. The IC50 values presented in Table 1 provide insight into the chelating potential of β-CBP. This is attributed to β-CBP's ability to reduce the concentration of catalyzing transition metal ions involved in lipid peroxidation (Ayala et al., 2014). Chelating agents are valuable as secondary antioxidants due to their capacity to lower the redox potential, thus stabilizing the oxidized form of the metal ion (Gulcin & Alwasel, 2022; Timoshnikov et al., 2022). Figure 1 demonstrates the results of the reducing power of β-CBP. A compound's reducing capacity serves as an indicator of its antioxidant activity (Munteanu & Apetrei, 2021). Both the ABTS and FRAP assays evaluate the product's radical scavenging and ferric reducing ability based on their Trolox equivalent antioxidant capacity (TEAC) values (Munteanu & Apetrei, 2021).

The alkaline DMSO, used as a superoxide-generating system, reacts with NBT to yield colored diformazan (Kumar et al., 2019). A decrease in absorbance at 560 nm within the presence of antioxidants indicates the consumption of superoxide radicals in the reaction mixture (Kumar et al., 2019). Figure 2 depicts the comparative superoxide radical scavenging ability of β-CBP. Superoxide anion is the most prevalent free radical in vivo and acts as a precursor for other reactive oxygen species (ROS), including hydrogen peroxide, hydroxyl radicals, and singlet oxygen, all of which can react with biological molecules and induce tissue damage. Therefore, under conditions of oxidative stress, the concentration of superoxide anions is of great significance (Birben et al., 2012).

The results reveal that β-CBP (20 mg/kg) effectively increased non-protein thiol levels in penile tissues of PD-induced rats compared to sildenafil (SD). This finding suggests that β-CBP may enhance non-protein thiol levels, potentially fortifying the antioxidant defense system and protecting penile tissues from oxidative damage. Non-protein thiols, such as glutathione (GSH), are abundant within cellular compartments and possess the capacity to donate electrons, detoxify lipid peroxides, and hydrogen peroxides, thus preventing the initiation of lipid peroxidation (Birben et al., 2012).

The study suggests that plants and/or plant foods rich in β-Caryophyllene could be promising sources of dietary phytochemicals for the management of erectile dysfunction.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Olopade E.O., and Adefegha S.A. The first draft of the manuscript was written by Olopade E.O., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

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The authors declare no competing interests.

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Ameliorative role of β-Caryophyllene on antioxidant biomarkers in Paroxetine induced erectile dysfunctional rats

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Abstract

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Introduction

MATERIALS AND METHODOLOGY

RESULTS

In vitro antioxidant potentials of β-Caryophyllene

Effects of β-Caryophyllene on antioxidant enzymes

DISCUSSION

Conclusion

Declarations

References

Additional Declarations

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