Sci. Aging Knowl. Environ., 4 May 2005
Vol. 2005, Issue 18, p. pe12
[DOI: 10.1126/sageke.2005.18.pe12]

PERSPECTIVES

Carnosine: A Versatile Antioxidant and Antiglycating Agent

V. Prakash Reddy, Matthew R. Garrett, George Perry, and Mark A. Smith

The authors are in the Department of Chemistry, University of Missouri-Rolla, Rolla, MO 65409, USA (V.P.R.), and the Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA (M.R.G., G.P., and M.A.S.). E-mail: preddy{at}umr.edu (V.P.R.); mark.smith{at}case.edu (M.A.S.)

http://sageke.sciencemag.org/cgi/content/full/2005/18/pe12

Key Words: advanced glycation end products • Alzheimer's disease • antioxidant • carnosine • DNA damage • oxidative stress

Introduction

Oxidative stress is involved in a variety of pathological conditions, including cataracts, diabetes, atherosclerosis, and Alzheimer's disease (AD; see "Detangling Alzheimer's Disease"). The intracellular accumulation of advanced glycation end products (AGEs), which are end products of the nonenzymatic glycation of proteins, has also been shown to be involved in these diverse pathologies (1-6). Further exacerbating oxidative stress, AGEs react with transition-metal ions such as Cu2+ or Fe2+, which are elevated in disease (7, 8). Thus, a variety of antioxidants and deglycating agents have been developed with the goal of halting oxidative stress and minimizing the formation of AGEs, and carnosine ({beta}-alanyl-L-histidine) (Fig. 1) is a naturally occurring dipeptide with the ability to multitask as an antioxidant and a deglycator. Although structurally simple, carnosine's mechanism of action as a deglycating agent or antioxidant remains unknown. In the human body, carnosine is found in excitable muscle and nervous tissues (olfactory receptor neurons outside the brain and glial cells within the brain) in concentrations as high as 20 mM, being synthesized from its constituent amino acids, {beta}-alanine and L-histidine, by the enzyme carnosine synthetase (9-11). Although the exact biochemical function of carnosine is uncertain, it has been shown to function as an antioxidant (12, 13) and as a neurotransmitter (14) in vivo.



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Fig. 1. Chemical structure of carnosine and selected carnosine analogs.

 
Maillard Reactions and AGEs

The carbonyl groups of reducing sugars react with side-chain amino groups of proteins (such as the {epsilon}-amino group of lysine or amidino group of arginine) to give a variety of products, initially proceeding through the formation of Schiff bases (the imines derived from the reaction of carbonyl groups with primary amino groups) and through Amadori rearrangements (see Fig. 2 in "Wake Up and Smell the Maillard Reaction"). Further glycoxidative degradation of the glycated proteins gives rise to 1,2-dicarbonyl compounds, which then react with other proteins, resulting in the formation of protein-protein cross-links, also known as AGEs. The complex series of reactions responsible for the formation of the AGEs, which are usually fluorescent, intensely colored compounds, is known collectively as the Maillard reaction (Fig. 2) (see "Wake Up and Smell the Maillard Reaction").



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Fig. 2. Maillard reaction of reducing sugars with proteins to give AGEs (protein cross-links). The formation of reactive 1,2-dicarbonyl compounds such as methylglyoxal is the primary event in Maillard reactions. These highly reactive dicarbonyl compounds then initiate further reactions with neighboring proteins, resulting in the formation of protein cross-links. Carnosine attenuates the formation of AGEs, presumably by sequestering the reactive 1,2-dicarbonyl compounds, although the structures of the adducts have not yet been characterized. AGEs include CML, pentosidine (arginine-lysine cross-link), MOLD (methylglyoxal-lysine dimer), and GOLD (glyoxal-lysine dimer) (1).

 
Although the pathological implications of AGEs remain open to debate, overwhelming evidence suggests that AGEs can serve as markers of pathophysiological conditions in age-related diseases. Indeed, the formation of AGEs increases with an organism's physiological age, as it does with the progression of pathological conditions such as diabetes (see Obrenovich and Monnier Perspective), cataracts, and atherosclerosis. The relationship of AGEs to the onset of AD has been demonstrated by Smith, Cerami, and their respective coworkers through immunochemical studies (see "Glycation Stimulates Amyloid Formation"): AGE-modified microtubule associated protein (MAP) tau protein and amyloid-{beta} peptide (A{beta}, derived from the amyloid precursor protein APP )--the two major pathological hallmarks of AD--have both been identified immunohistochemically in AD brains, with notable localization in senile plaques and neurofibrillary tangles (NFTs) (3-6). AGEs also exhibit cytotoxic effects in cultured cortical neurons and AD brain tissue (15, 16).

Transition Metals and Oxidative Stress in Alzheimer's Disease

Oxidative stress has been recognized as one of the causative factors of AD, although antioxidant therapy has so far met with little success in treating the disease. Because oxidative stress is also associated with various other pathologies, it is important that we understand the mechanisms of oxidative homeostasis in cells in order to be able to design effective antioxidants for the possible treatment of AD. The accumulation of iron and copper that is observed in AD (see "Mindful of Metal") emphasizes the importance of the generation of free radical species such as toxic hydroxyl radicals (for example, through the Fenton reaction--reduction of H2O2 catalyzed by transition-metal ions such as Fe2+), which are well appreciated for their involvement in lipid peroxidation and also damage proteins and DNA (7). It has been found that redox-active iron is associated with amyloid plaques and NFTs in brain tissue from AD patients; characterization of iron-binding sites has shown that binding is dependent on the available histidine residues and on protein conformation (8). MAP tau has also been found to be capable of adventitious binding of redox-active copper and iron (8). It is important to point out, however, that while NFTs and amyloid plaques have been shown to contain transition metals, these may exert either a pro-oxidant or antioxidant effect, depending on the local balance between cellular oxidants and reductants at the site of lesions.

AGEs activate receptors known as receptors for advanced glycation end products (RAGEs, see Monnier Perspective), which are linked to increased production of reactive oxygen species (ROS). RAGE is a multiligand binding member of the immunoglobulin superfamily of cell-surface molecules, for which AGEs act as ligands (17). AGEs and RAGEs accumulate in amyloid plaques in AD, where sources of redox-active iron and copper are abundant, exacerbating oxidative stress. For example, it has been shown that there is a direct biochemical link between AGEs and the formation of lipid peroxidation products (such as trans-4-hydroxy-2-nonenal, or HNE) in a neuronal cell line (18). AGEs also activate glial cells to produce superoxide, nitric oxide, and neurotoxic cytokines such as TNF-{alpha} (19). Thus, AGE inhibitors may prove to be viable candidates for the treatment of AD, with the potential to attenuate the progress of the disease not only as antioxidants but also as antiglycating agents.

Carnosine as an AGE Inhibitor

Recently there has been interest in designing compounds that prevent the formation of AGEs; aminoguanidine, D-penicillamine, thiamine pyrophosphate, and pyridoxamine are all examples of such AGE inhibitors (20-22). Carnosine also shows AGE inhibitory action: Protein cross-links induced by methyglyoxal, an oxoaldehyde formed during the Maillard reaction, were found to be eliminated in the presence of carnosine (23). Although the mechanism by which carnosine inhibits the formation of AGEs remains to be elucidated, it is likely that the free amino group derived from {beta}-alanine ({beta}-aminopropionic acid or 3-aminopropanoic acid) competes with the amino groups of proteins in their reaction with reactive 1,2-dicarbonyl compounds. However, {beta}-alanine itself has a much smaller AGE inhibitory effect than carnosine, and the neighboring imidazolium moiety (Fig. 1) of carnosine shows synergistic activity in the stabilization of Schiff bases derived from carnosine and 1,2-dicarbonyl compounds (23). A variety of modified versions of carnosine, such as anserine ({beta}-alanyl-3-methyl-L-histidine), carcinine ({beta}-alanylhistamine), and homocarnosine ({gamma}-aminobutyrylhistidine), also show a similar ability to inhibit AGE formation (Fig. 1) (24).

If carnosine has a major role in preventing AGE formation in vivo, the occurrence of intracellular AGEs should correlate inversely with the concentration of carnosine. This parallel cannot easily be demonstrated under in vivo conditions, however, because other established pathways inhibit AGE formation. For example, vitamins C, E, and A are all effective radical scavengers and attenuate glycoxidation, thereby leading to reduced formation of AGEs (25, 26). The biological coenzymes pyridoxamine and thiamine pyrophosphate are also effective inhibitors of AGE formation from post-Amadori products (22, 27). AGEs are generally viewed as markers of aging, however, as the longevity of mammalian species shows a positive correlation with intramuscular concentrations of carnosine (28).

What do we know about the detailed mechanism of action of carnosine? Glycoxidation usually results in an increased carbonyl content of modified proteins, which leads to formation of cross-links with other neighboring proteins. Incubation of 14C-labeled carnosine with methylglyoxal-treated ovalbumin in vitro resulted in a decrease in the carbonyl content of the protein, with concomitant incorporation of radioactivity in the modified ovalbumin. Conversely, competitive experiments in the presence of [14C]-lysine and unlabeled carnosine showed that the presence of carnosine caused a decrease in the amount of [14C]-lysine in modified ovalbumin. Thus, carnosine competes effectively with the amino groups of lysine residues to form Schiff bases, acting as an effective AGE inhibitor. Further, in the presence of carnosine, the ability of methylglyoxal-treated ovalbumin to form cross-links to a second protein, {alpha}-crystallin, is dramatically reduced, showing the carbonyl sequestering ability of carnosine (29).

Detoxification of Advanced Lipid Peroxidation End Products by Carnosine

Lipid peroxidation, initiated by the reaction of ROS with polyunsaturated fatty acids (PUFAs), generates a variety of toxic carbonyl compounds such as HNE, trans-4-oxo-2-nonenal (4-ONE), and malondialdehyde (MDA), which are prone to react with the side-chain primary amino groups of proteins. The products of such protein modification reactions are known collectively as advanced lipoxidation end products (ALEs). Some ALEs, such as N{epsilon}-(carboxymethyl)lysine (CML) and N{epsilon}-(carboxyethyl)lysine (CEL), are derived through either glycoxidation or lipid peroxidation reactions (30). PUFA side chains are constituents of a variety of membranes and lipoproteins, and thus lipid peroxidation, in addition to glycoxidation, is a major pathway for protein modification (31).

HNE is implicated in a variety of pathologies (see Praticò Review) (32, 33) and is involved in the cross-linking of a variety of intracellular proteins. It can also attack the nucleotide bases of DNA, causing transversion mutations (34). HNE is elevated in AD patients as compared with controls, and it may induce neuronal death by altering the ATPases involved in calcium homeostasis (35). HNE can be detoxified by carnosine through Michael adduct formation, involving the primary amino group of carnosine's {beta}-alanyl moiety, or through the histidine residue (36). Other products of the reaction, such as the Schiff base and subsequently cyclized products, have been identified in the course of in vitro experiments (Fig. 3) (37). Although detoxification of HNE through its reaction with the antioxidant glutathione (see Nicholls Perspective) may be an important alternative pathway in vivo, reduced amounts of glutathione present under conditions of increased oxidative stress require that other means are available for detoxifying HNE. Thus, carnosine plays a vital role in controlling intracellular HNE concentrations.



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Fig. 3. Detoxification of HNE by carnosine and glutathione (GSH).

 
Carnosine also protects against MDA (which is found ubiquitously in cells), an agent that would otherwise be able to induce protein damage and cellular toxicity (38). Elevated levels of MDA are found in the brains of AD patients (39). By way of in vitro experiments, it has been shown that MDA can modify MAP tau and A{beta} through reactions of the carbonyl groups of MDA with the {epsilon}-amino group of lysine and the amidino group of arginine (40). Although adducts of carnosine and MDA have not been isolated, it is likely that the amino group of the {beta}-alanyl portion of carnosine reacts with carbonyl groups of MDA to form dimeric compounds.

Role of Carnosine in Attenuating DNA Damage

In general, raised intracellular oxidative stress results in widespread DNA damage (see Skinner and Turker Review). DNA can be damaged by ROS (such as H2O2, superoxide, hydroxyl radicals, and HOCl) (see "The Two Faces of Oxygen"), reactive nitrogen species (RNS, such as peroxynitrite, O=N-OO), HNE, or malondialdehyde (41). Studies of the effect of carnosine on DNA damage are limited, but there are indications that it may attenuate DNA cleavage induced by AGEs in the presence of Fe3+ (42). It is likely that carnosine is involved in minimizing DNA damage by sequestering ROS, RNS, and lipid peroxidation products such as HNE and MDA. In addition, carnosine may alleviate oxidative stress by a variety of mechanisms, including transition-metal ion chelation and the trapping of protein carbonyls. For example, by the selective sequestration of transition-metal ions (such as Cu+ and Fe2+) by carnosine, the Fenton reaction leading to production of reactive hydroxyl radicals can be attenuated. The accumulation of protein carbonyls correlates with the extent of oxidative stress and glycation, and the free amino group of carnosine may react with protein carbonyls, thus contributing to the reduced formation of AGEs.

Carnosine has also been linked to cell growth and senescence in culture, because human diploid fibroblast cells grown in medium including 20 mM carnosine show a reduced rate of telomere shortening and an extended life span in culture (43).

Conclusion

The naturally occurring compound carnosine shows unique properties as an antioxidant and antiglycating agent. Although the exact mechanisms by which carnosine sequesters ROS and RNS have not been elucidated, carnosine is implicated in neuroprotection in susceptible neurons where damaging free radicals are produced. Carnosine also reacts with HNE, a deleterious lipid peroxidation product, to form adducts, several of which have been characterized by in vitro studies. It is presumed that similar adduct formation with 1,2-dicarbonyl compounds derived from Maillard reactions may inhibit the formation of AGEs, as carnosine can effectively compete with lysine for Maillard-derived protein carbonyl groups. Carnosine is also able to form complexes with redox metal ions, which are involved in the formation of ROS and RNS, thus acting as an antioxidant. Conversely, by sequestering metal ions, carnosine can prevent glycoxidation, thereby acting as an AGE inhibitor.

Currently there are clinical trials under way involving the use of carnosine to treat cataracts and other diseases, based on its antioxidant properties (44-46). AGEs and oxidative stress are also known to play a role in the pathology of AD. However, although carnosine is already a popular nutritional supplement, its possible value as an anti-aging agent, or even as a candidate for attenuating or treating AD, should be viewed with caution until further studies throw light on the underlying mechanisms of oxidative homeostasis in vivo.


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  47. Support of our work by the American Chemical Society Petroleum Research Fund (PRF 39643-AC, to V.P.R.), the Alzheimer's Association (IIRG-03-6263, to M.A.S.), and the National Institutes of Health (AG14249, to G.P.) is gratefully acknowledged.
Citation: V. P. Reddy, M. R. Garrett, G. Perry, M. A. Smith, Carnosine: A Versatile Antioxidant and Antiglycating Agent. Sci. Aging Knowl. Environ. 2005 (18), pe12 (2005).




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