Enalapril attenuated CFA provoked arthritic manifestation by modulating proinflammatory and anti-inflammatory cytokine network
Introduction
Angiotensin converting enzyme (ACE), a halide-activated peptidase, catalyzes the breakdown of substance P and bradykinin as well as responsible for converting angiotensin I to angiotensin II. Angiotensin II, the primary hormone of the rennin-angiotensin system (RAS), exhibits both autocrine and paracrine proinflammatory characteristics [1]. The immune system, as well as inflammatory and degenerative processes, appear to be directly influenced by RAS. T-cells, macrophages, natural killer (NK) cells and dendritic cells are immune system cells that possess angiotensin receptors, thereby, respond to AngII [2]. By promoting the proliferation of progenitor cells, adhesion molecules, and P-selectin, AngII promotes the production of more circulating monocytes. Ang II also regulates the circulation and local concentrations of immune cells [3], [4]. AngII also induces adhesion molecules and P-selectin, which results in the accumulation of immune cells locally. According to these results, AngII is a chemoattractant hormone. It is therefore not surprising that AngII is widely asserted to have a significant role in a variety of autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis [3]. Important pro-inflammatory indicators like interleukin (IL)-6, 8, and TNF-α are upregulated locally by AngII accumulation, and the level of reactive oxygen species is also increased [5]. The key elements of pathological RAS stimulation causing vascular inflammation are NF-ĸB activation and an increase in CRP through ERK1/2 JNK signaling [6]. Furthermore, the widespread distribution of all RAS system components in RA suggests that locally generated Ang II in inflamed knee joints has therapeutic and pathological implications for RA [7]. All these evidences points out a strong implication of RAS and Ang II in the pathobiology of RA. Thereby targetting Ang II might turned out to be a suitable strategy for treating RA manifestations.
Variable outcomes were obtained for earlier clinical studies conducted on ACE inhibitors for their probable role in RA [8], [9], [10]. According to one of preclinical study, the inhibitory action of captopril and quinapril on TNF-α was hypothesized to be the cause of their anti-arthritic efficacy. One study also suggested the anti-arthritic potential of enalapril, but they only estimated the level of IL-1β in arthritic rats. Another study revealed the anti-inflammatory potential of enalapril by modulating IL-1β level while estimating the effect of enalapril on frailty development [11]. Some other studies also documented the anti-inflammatory potential of enalapril [12], [13]. Thus, it can be concluded that enalapril has considerable anti-inflammatory potential that can contribute towrds its ant-arthritic efficacy. However, the exact mechanism by which enalapril might exert its anti-arthritic attribute remained to be identified. Thereby, in the current investigation, we used three different doses of enalapril and targeted a number of pro-inflammatory and anti-inflammatory mediator along with some oxidative stress parameters to point out a more detailed anti-arthritic mechanism of enalapril.
Section snippets
Experimental animals and housing condition
Sprague-Dawley rats weighing 200–250 g were used and kept at a temperature of 25 ± 2 °C under a 12-h light/dark cycle. Before the start of the experiments, there was a seven-day acclimatization phase. Rats were given unlimited access to food and water. The Institutional Animal Ethical Committee of the College of Pharmacy at the University of Sargodha in Pakistan gave its prior consent for the experiments (permission number 22A28 IEC/UOS).
Assessment of enalapril's anti-arthritic potential against CFA instigated arthritis
Arthritis was prompted in all experimental animals by
Paw edema suppression by enalapril treatment
To evaluate the anti-arthritic effect of enalapril CFA induced arthritic model was employed. Outcomes of the study demonstrated a dose dependent anti-arthritic efficacy of enalapril. Enalapril at all the three selected doses (2, 4 and 8 mg/kg) remarkably inhibited paw edema provoked by CFA. At the end of the study period, 28th day, enalapril (8 mg/kg) demonstrated 70.82 % (p˂0.001) inhibition of paw edema compared to arthritic control group. Likewise, enalapril at the dose of 4 mg/kg and
Discussion
Enalapril was employed as an anti-arthritic agent in the current investigation, and CFA induced arthritic model evaluated anti-arthritic efficacy. Enalapril's impact on experimental arthritis has received little attention, although Nikbakht and colleagues' (2007) findings suggest that it can modulate the symptoms of antigen-induced arthritis in rabbits by affecting only IL-1β. Thereby in current investigation, a number of parameters were assessed to point out a detailed mechanism for
Conclusion
Outcomes of the current investigation demonstrated the anti-arthritic activity of enalapril by employing CFA induced arthritic model. Enalapril had suppressive effect on paw inflammation and arthritic score. The body weight and radiological alterations improved with enalapril. Additionally, it normalized the biochemical and hematological markers. Enalapril also demonstrated its antioxidant potential by enhancing the level of CAT, SOD and GSH while suppressing MDA levels. Enalapril's
Funding
This work was funded by Deanship of Scientific Research at Jouf University under Grant number (DSR2022-RG-0145).
Declaration of competing interest
Authors have no conflict of interest to declare.
References (50)
Inflammation and angiotensin II
Int. J. Biochem. Cell Biol.
(2003)The pro-inflammatory cytokines in COVID-19 pathogenesis: what goes wrong?
Microb. Pathog.
(2021)Angiotensin II induces C-reactive protein expression through ERK1/2 and JNK signaling in human aortic endothelial cells
Atherosclerosis
(2010)Angiotensin II triggers knee joint lesions in experimental osteoarthritis
Bone
(2021)Ephedra gerardiana aqueous ethanolic extract and fractions attenuate freund complete adjuvant induced arthritis in Sprague dawley rats by downregulating PGE2, COX2, IL-1β, IL-6, TNF-α, NF-kB and upregulating IL-4 and IL-10
J. Ethnopharmacol.
(2018)- et al.
Anemia of inflammation
Blood
(2019) - et al.
The Effect of Enalapril on Inflammation and IL-1Beta and IL-8 Production in Chronic Arthritis
(2007) The tissue renin-angiotensin system and its role in the pathogenesis of major human diseases: quo vadis?
Cells
(2021)- et al.
Angiotensin II in inflammation, immunity and rheumatoid arthritis
Clin. Exp. Immunol.
(2015) Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and the risk of developing rheumatoid arthritis in antihypertensive drug users
Pharmacoepidemiol. Drug Saf.
(2012)