*4.2.1 Peroxidation of lipids*

### *4.2.1.1 4-HNE and MDA*

The 4-HNE is one of the aldehydes specific to lipid peroxidation. 4-HNE is believed to be predominantly responsible from the cytopathologic effects seen during OS. Any factor compatible with stress or activity of antioxidant enzymes may trigger potentially dangerous metabolic pathway of peroxidative damage [50]. Our results showed that the level of HNE protein adducts was significantly increased on day 14 in rat AA [51]. The level of malondialdehyde (MDA) in the plasma of arthritic animals was also elevated [52–54] (**Table 1**). He et al. demonstrated an increased level of MDA in serum of AIA rats, which was significantly decreased by the administration of anthocyanins from cherries [53]. AA induced in male Sprague-Dawley rats increased plasma MDA levels, levels of glutathione, enzyme activities of SOD and GPx were decreased [55]. Also, Wang et al. demonstrated a significant increase of MDA and moreover nitrites in plasma of AIA rats [56]. Levels of anti-type II collagen antibody, nitrite/nitrate, and lipid peroxidation (levels of 4-HNE and MDA) were determined in the serum, joints, and brain. CIA elevated levels of nitrite/nitrate and 4-HNE and MDA levels in serum and the brain [57]. We also measured an increased levels of 4-HNE and MDA in plasma and the brain of AIA rats (**Tables 1** and **2**) [58].

#### *4.2.1.2 Isoprostanes*

Isoprostanes are a complex family of compounds produced from arachidonic acid via a free radical-catalyzed mechanism. They are reliable markers of lipid peroxidation. A strong link between lipid peroxidation and diseases associated with ischemia-reperfusion, atherosclerosis, and inflammation has been suggested by


*Values are expressed as average standard error of mean, statistical significance (ANOVA-Tukey-Kramer post hoc test): \*\*p < 0.01, \*\*\*p < 0.01 vs. CO.*

#### **Table 1.**

*Markers of oxidative stress (malondialdehyde (MDA), 4-hydroxynonenal (HNE), and protein carbonyls) in plasma of arthritic animals measured on day 28.*

*Impact of Oxidative Stress on Inflammation in Rheumatoid and Adjuvant Arthritis: Damage… DOI: http://dx.doi.org/10.5772/intechopen.89480*


**Table 2.**

**4.2 Oxidative stress in adjuvant arthritis**

*Animal Models in Medicine and Biology*

type of therapy.

*4.2.1 Peroxidation of lipids*

*4.2.1.1 4-HNE and MDA*

brain of AIA rats (**Tables 1** and **2**) [58].

*4.2.1.2 Isoprostanes*

*test): \*\*p < 0.01, \*\*\*p < 0.01 vs. CO.*

*plasma of arthritic animals measured on day 28.*

**Table 1.**

**202**

In the development of AIA, not only immunological and inflammatory pathological changes are involved, but also the redox homeostasis is shifted toward increased production of ROS and RNS. Overproduction of ROS and RNS damages lipids, proteins, and DNA (also exhausts the natural enzymatic and nonenzymatic antioxidant defense), which is possible to detect with different markers of oxidation in biological structures. In human RA OS-mediated damage to lipids, proteins, and DNA and changes in enzymatic and nonenzymatic antioxidant defense are extensively studied. AIA in animals resembles the OS caused damage in human rheumatic diseases; therefore, it is a very useful tool to study process of OS during autoimmune diseases. Since there has been no standard therapy to reduce OS damage in diseases established yet, AIA could be a promising candidate for developing this

The 4-HNE is one of the aldehydes specific to lipid peroxidation. 4-HNE is believed to be predominantly responsible from the cytopathologic effects seen during OS. Any factor compatible with stress or activity of antioxidant enzymes may trigger potentially dangerous metabolic pathway of peroxidative damage [50].

Isoprostanes are a complex family of compounds produced from arachidonic acid via a free radical-catalyzed mechanism. They are reliable markers of lipid peroxidation. A strong link between lipid peroxidation and diseases associated with ischemia-reperfusion, atherosclerosis, and inflammation has been suggested by

**Oxidative stress in plasma MDA (μg/mL) HNE (ng/mL) Protein carbonyls (nmol/mL)**

*Markers of oxidative stress (malondialdehyde (MDA), 4-hydroxynonenal (HNE), and protein carbonyls) in*

CO 2.4 0.39 1.54 0.16 391.2 14.34 AIA 5.79 0.44\*\*\* 2.5 0.19\*\*\* 457.72 11.09\*\* *Values are expressed as average standard error of mean, statistical significance (ANOVA-Tukey-Kramer post hoc*

Our results showed that the level of HNE protein adducts was significantly increased on day 14 in rat AA [51]. The level of malondialdehyde (MDA) in the plasma of arthritic animals was also elevated [52–54] (**Table 1**). He et al. demonstrated an increased level of MDA in serum of AIA rats, which was significantly decreased by the administration of anthocyanins from cherries [53]. AA induced in male Sprague-Dawley rats increased plasma MDA levels, levels of glutathione, enzyme activities of SOD and GPx were decreased [55]. Also, Wang et al. demonstrated a significant increase of MDA and moreover nitrites in plasma of AIA rats [56]. Levels of anti-type II collagen antibody, nitrite/nitrate, and lipid peroxidation (levels of 4-HNE and MDA) were determined in the serum, joints, and brain. CIA elevated levels of nitrite/nitrate and 4-HNE and MDA levels in serum and the brain [57]. We also measured an increased levels of 4-HNE and MDA in plasma and the

*Markers of oxidative stress (malondialdehyde (MDA) and 4-hydroxynonenal (HNE) in the brain of arthritic animals measured on day 28).*

elevated levels of F2-isoprostanes observed in such diseases. Quantification of F2 isoprostanes as pathophysiological markers is suitable for the investigation of lipid peroxidation in human diseases and provides an interesting biomarker of antioxidant efficacy in diseases where OS might be involved [59]. There are only few evidences about F2-isoprostanes in animal models of RA. In one of our previous experiments, we have measured an elevated level of F2-isoprostanes in plasma of AIA rats, which were significantly increased compared to control healthy animals [60]. In a CIA model, authors investigated the ability of grape seed proanthocyanidin extract (GSPE) to reduce the development of mice arthritis. They have found that CIA significantly increased the level of 8-isoprostane in plasma. Plasma levels of 8-isoprostane and serum level of collagen type II-specific IgG2a in GSPEtreated mice were significantly decreased than those in the control mice [61]. Authors demonstrated that F2-isoprostanes are increased also in the urine of CIA mice [62]. F2-isoprostanes as an important marker of lipid peroxidation should be more extensively studied in AIA animal models, to obtain a better picture about the similarity with human RA.
