Introduction

Advanced lipoxidation end-products (ALEs) are defined as adducts and cross-links that are made by the reaction of produced reactive carbonyl species (RCS) in peroxidation with DNA, proteins, and aminophospholipids in a nonenzymatic process [1]. Malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), 4-hydroxyhexanal (4-HHE), and acrolein (ACR) are the well-known ALEs. ALE formations demolish biological molecules and processes including proteins, loss of enzymatic activity, and DNA damage and mutagenesis [1, 2] that induce many chronic diseases, such as diabetes, rheumatoid arthritis, and neurodegenerative, cardiovascular, and kidney diseases [3, 4].

Carnosine (βalanyl-Lhistidine) that was discovered by a Russian scientist as a constituent of brain and muscular tissues is synthesized by carnosine synthase [5]. Acting as an antioxidant, regulating immune response, tissue pH buffering, chelating heavy metals, and rejuvenating senescence are some of the potential properties of carnosine [6, 7], and in humans positive results of carnosine have been investigated in heart failure and psychology and psychiatry [8, 9].

Regarding the increased prevalence of chronic diseases and the direct effect of oxidative stress, the review of the antioxidant properties of carnosine can be useful for the use of this dipeptide for therapeutic purposes. In our previous studies, the effect of carnosine on the advanced glycation end-products in animals and cells was determined [10, 11]. We will now consider the possibility of the effect of carnosine on advanced lipoxidation end-products in various problems.

Methods

Data for this review were attained electronically from PubMed, Scopus, and Google scholar. The publication year of conducted studies was considered from 2005 and only English articles were analyzed. The keywords used for the search were “carnosine and advanced lipoxidation end products,” “carnosine and ALE,” “carnosine and malondialdehyde,” and “carnosine and MDA.”

Results

Twenty related articles were retrieved on carnosine effects on and ALEs. These studies were divided into eight categories of diabetes, liver, aging, muscle, brain, renal, heart, and other problems. These studies were assembled in Table 1.

Table 1 Studies of carnosine effects on advanced lipoxidation end-products
Full size table

Kumral et al. [29] after supplementation of 250 mg/kg carnosine found that carnosine alone or with vitamin E decreased thiobarbituric acid reactive substances (TBARS), diene conjugate (DC), and protein carbonyl (PC) in the heart, liver, and kidney. Their results indicated that carnosine alone or with vitamin E protects against toxicity in tissues and could be a useful supplement to the prevention of toxic complications of doxorubicin in chemotherapy.

In a study in 2016, 10 mg/kg carnosine supplementation on 28 rats for 8 weeks showed that carnosine treatment increased the contents of total antioxidant capacity in the intervention group and decreased MDA. Carnosine also prevented the decrease in albumin and the level of total protein and stimulated hepatic enzymes. They concluded that carnosine could prevent acetate-induced hepatotoxicity by enhancing antioxidant capacity and inhibition of lipid peroxidation [12].

Zhang et al. [21] after supplementation of carnosine to 54 experimental subarachnoid hemorrhage rats found that the level of MDA, 3-nitrotyrosine (3-NT), and 8-hydroxydeoxyguanosine (8-OHDG) were significantly reduced in brain cortex at 48 h. Also, in the similar study, Xie et al. [20] found that carnosine treatment significantly diminished the increased level of ROS, MDA, 3-NT, and 8-OHDG induced by intracerebral hemorrhage. These two findings indicated that carnosine supplementation after brain injury may provide neuroprotection.

Yapislar and Taskin [23] after supplementation of 50 mg/kg carnosine in nephrectomized rats for 15 days found that this treatment augmented the level of nitric oxide (NO), reduced the level of MDA, and improved RBC deformability and can have beneficial effects on chronic kidney diseases.

In the study by Dursun et al. [26] on 40 adriamycin-induced cardiomyopathic rats for 2 weeks after supplementation of 10 mg/kg/day carnosine, the level of MDA, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), creatine kinase, and catalase (CAT) was attenuated. Evran et al. [25] found that carnosine supplementation on isoproterenol-induced myocardial-infarcted rats decreased plasma lactate dehydrogenase and aspartate transferase activities, cardiac MDA, and PC and increased the antioxidant enzymes activities. But, the plasma and erythrocyte MDA and PC levels did not change.

Doğru-Abbasoğlu et al. [27] after treatment of rats by carnosine found that carnosine supplementation did not change hypertriglyceridemia, insulin resistance, or liver’s antioxidant system, but it declined lipid peroxidation in the of high fructose diet rats. However, carnosine combined with tocopherol attenuated inflammation, insulin resistance, and lipid peroxidation.

In the other study on 72 recipient pigs of 0, 25, 50, or 100 mg/kg carnosine supplement for 8 weeks, supplementation with 25 mg/kg carnosine did not affect Ca-ATPase activity, MDA, and PC in skeletal muscle. In the 100 mg/kg carnosine group, the MDA concentrations were lower than that of the 0 or 25 mg/kg but there were no changes in muscle MDA between the recipient of 50 and 100 mg/kg carnosine at 24 h and 48 h postmortem [19].

In the other study on 32 testis ischemic rats, Abbasoğlu et al. [30] found that, however, carnosine supplementation in a dose of 250 mg/kg carnosine did not change TBARS, SOD, and GPx, but it decreased the elevated level of DC and PC and regulated spermatogenesis in these rats.

Possible Mechanism

Anti-oxidative activity of carnosine is more than both β-alanine and L-histidine. Thus, the efficient antioxidant ability of carnosine is principally dependent on the linkage of β-alanyl and L-histidine [31].

Radical Scavenging

The powerful antioxidant activity of carnosine can be shown by its action as an electron donor to singlet oxygen, superoxide, and hydroxyl radicals [32, 33]. Imidazole rings are recognized to counter with singlet oxygen but carnosine as a compound consisting of imidazole ring was stated to react more than twofold faster than other L-histidine components [34]. Also, carnosine might increase the activity of antioxidant proteins and enzymes like glutathione, GSH-Px, and SOD and play a significant role in reducing products of lipid peroxides [35, 36]. On the other hand, carnosine or related peptides chelate iron or copper (metal ions such as iron are the common producers of free radicals) hence blocking free radical production [37, 38].

Reaction with Aldehydes

Lipid peroxidation produces a lot of aldehyde products. Carnosine reacts with these kinds of toxic compounds, forms protein-carbonyl-carnosine adducts, and thereby quashes their toxicities [39, 40]. Aldini et al. [41] confirmed the suppressive ability of this dipeptide on PC in obese rats. These findings were consistent with the study of Hipkiss et al. [42] which used “carnosinylated” protein term for the protein-carbonyl-carnosine adducts. Carnosine-HNE adducts were found in both animals and humans [43]. It is suggested that carnosine facilitate the proteolytic elimination of modified protein on proteasomes [44].

Conclusion

The results of this study showed that carnosine has the potential to reduce the plasma and tissue levels of the ALEs and oxidative stress, and can be effective in oxidative-related problems such as cerebral, cardiac, and renal disease, although there is a limitation in human study.