Anti-inflammatory effect of omega-7 against doxorubicin-induced cardiotoxicity in male rats: An observational study

Introduction

Doxorubicin is a highly effective chemotherapeutic agent used to treat several types of cancer, such as hematogenous and solid cancers.¹ Unfortunately, this medication's clinical utility is constrained due to its adverse effects, particularly cardiotoxicity, which may include cardiac arrhythmias, congestive heart failure, left ventricular dysfunction, and cardiomyopathy.² It has been suggested that oxidative stress, apoptosis, autophagy, and Endoplasmic reticulum (ER) stress are the mediators of Doxorubicin-induced cardiac damage.³ Doxorubicin-induced cardiac damage is also influenced by inflammation. It has been demonstrated that doxorubicin therapy significantly increases the expression of tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β, and IL-6.⁴ In addition, phosphokinase C (PKC) has been suggested to act as an intracellular signaling mediator for TNFα activity, which causes cytotoxicity and apoptosis in various cell types.⁵ The membranes of cells and organelles are usually permeable to fatty acids, and the administration of unsaturated fatty acids such as omega-3, -6, and -9 fatty acids, or various combinations of these fatty acids, has been studied for its potential health benefits.⁶ It has also been suggested that omega-7 fatty acid supplements may affect serum inflammatory biomarkers.⁶ The primary components of omega-7 are palmitoleic acid (16:1, cis-9-hexadecenoic acid) and vaccenic acid [(11E)-11-octadecenoic acid] ERER, which are primarily found in cold-water fish and sea buckthorn berries.⁷ Omega-7 is a non-essential fatty acid in humans as it can be produced endogenously.⁸ The consumption of omega-7 fatty acids has been related to better health outcomes by increasing HDL cholesterol levels and decreasing LDL cholesterol levels.⁷ Earlier research has demonstrated that omega-7 fatty acids efficiently suppress H₂O₂-induced inflammatory factors such as prostaglandin E2 (PGE2), tumor necrosis factor- (TNF-α), and interleukin-1 (IL-1β).⁸ Nevertheless, the effects of omega-7 on the integrity of cardiac tissue are yet to be established. As a result, we want to look into whether omega-7 may prevent against doxorubicin-induced cardiotoxicity by reducing inflammation.

Methods

Results

Analysis of the data in Table 1 revealed a significant increase in lactate dehydrogenase (LDH) levels in group 2 (positive control) compared to group 1 (negative control) at p < 0.05. Despite the absence of a significant difference p > 0.05 in the level of LDH in group 3 (100 mg) when compared to group 2, the level of LDH decreased significantly p < 0.05 in group 4 (300 mg/kg omega-7) when compared to group 2. The level of creatinine kinase-MB (CK-MB) was significantly elevated in group 2 (positive control) compared to group 1 (p < 0.05). While there was no significant difference in the level of CK-MB between groups 3 (100 mg) and 2 (p > 0.05), the higher dose of omega-7 (300 mg/kg) in group 4 significantly decreased the level of CK-MB compared to group 2 (p < 0.05; Table 2).

The serum concentration of TNF-α was substantially elevated in the doxorubicin-treated group compared with the control group (p < 0.05; Figure 1). In contrast, the co-administration of omega-7 in groups 3 (100 mg/kg) and 4 (300 mg/kg) decreased TNF-α levels considerably compared to group 2 (positive control) p < 0.05. IL-6 levels were considerably elevated in group 2 (positive control) compared to group 1 (negative control) in Figure 2 (p < 0.05). In contrast, the co-administration of omega-7 in groups 3 (100 mg/kg) and 4 (300 mg/kg) substantially decreased IL-6 levels compared to group 2 (positive control) p < 0.05. Significantly more IL-1 was detected in group 2 (positive control) than in group 1 (positive control), p < 0.05. As demonstrated in Figure 3, the co-administration of omega 7 (100 mg/kg) in group 3 and (300 mg/kg) in group 4 decreased IL-1 considerably p < 0.05 compared to group 2 (positive control).

Figure 1. The effect of omega7 (100 mg/kg) and (300 mg/kg) on the level of TNFα in serum induced by doxorubicin (15 mg/kg, single dose).

Figure 2. The effect of omega7 (100 mg/kg) and (300 mg/kg) on the level of IL-6 in serum induced by doxorubicin (15 mg/kg, single dose).

Figure 3. The effect of omega7 (100 mg/kg) and (300 mg/kg) on the level of IL-1β in serum induced by doxorubicin (15 mg/kg, single dose).

Discussion

The high prevalence of cardiomyopathy and heart failure is the main side effect of doxorubicin usage.¹¹ According to several investigations, the production of reactive oxygen species (ROS) from doxorubicin redox activation contributes significantly to the cytotoxicity of doxorubicin.¹¹ Numerous other studies have concentrated on the signaling mechanism that causes doxorubicin-induced apoptosis.^12,13 Moreover, pro-inflammatory cytokines such as IL-6, TNFα, and IL-1β are implicated in activating inflammatory reactions.¹⁴ It has previously been noted that doxorubicin causes heart tissue to release more pro-inflammatory cytokines.¹⁵ In the present study, the administration of doxorubicin to rats resulted in cardiotoxicity, as evidenced by significant increases in LDH and CK-MB serum levels (Table 1), which have been utilized in various preclinical investigations to evaluate heart injury,^16,17 combined with a significant increase of serum levels of pro-inflammatory cytokines including TNFα, IL-1β, and IL-6; similar to other findings.^15,18

Pre-treatment with omega-7 in group 3 (100 mg/kg) caused a non-significant difference in LDH and CK-MB levels compared to the positive control group. However, pre-treatment with a larger dose (300 mg/kg) showed a significant reduction in LDH and CK-MB levels compared to group 2. This outcome is in line with earlier investigations into the effectiveness of polyunsaturated fatty acid as a cardioprotective subsistence.¹⁹

TNFα is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation and is in charge of several cell-signaling processes that result in necrosis or apoptosis.²⁰ From the study, the level of TNFα was significantly reduced in the omega-7 pretreated group (100 mg and 300 mg/kg), which is in line with other research about the anti-inflammatory effect of omega-7 in H₂O₂-treated cells.⁸ Interleukin-6 (IL-6) is known to regulate immune responses and is considered a potentially helpful indicator of immune system activity.²¹ Inflammation, infection, and cardiovascular disease may cause an increase in IL-6. IL-1β is a cytokine that plays a role in pain, inflammation, and autoimmune diseases.²² From the study, the levels of both IL-6 and IL-1β were significantly reduced in omega-7 treated groups (100, 300 mg/kg) compared to the positive control group. The result is consistent with another published study on omega-3 concerning those biomarkers.²³ However, the current study is the first to demonstrate the efficacy of omega-7 in lowering the elevated levels of IL -6 and IL -1β associated with doxorubicin-induced cardiotoxicity. The production of several cytokines, including TNFα, during the oxidative stress brought on by the doxorubicin therapy, served as a mediator for cytotoxicity.²⁴ It was discovered that omega-7, which was used in this study to protect the myocardial tissue from doxorubicin toxicity, inhibited the excessive release of TNFα through a mechanism linked to the suppression of the PKC enzyme responsible for the production of NF-kβ, the crucial signaling molecule in the pathway that releases TNFα.²⁵ Therefore, an appealing treatment strategy for treating doxorubicin-induced cardiotoxicity is to modify the expression of the cytokines.²⁶ The presentation of TNF and other inflammatory mediators during oxidative stress situations is inhibited by substances like omega-7, which may have potential therapeutic utility in this area.

Conclusion

The current discovery suggests that omega-7 may shield the myocardium against doxorubicin-induced damage by reducing the inflammatory response.