Key words

Sandra Budzeń

_{, Joanna Rymaszewska}

The Biological Role of Carnosine

and Its Possible Applications in Medicine

Rola biologiczna karnozyny i możliwości jej zastosowania w medycynie

1 _{PhD studies, Department of Physiotherapy, Wroclaw Physical Education Academy, Poland}

2 _{Research Unit of Consultation-Liaison Psychiatry & Behavioral Medicine, Department of Psychiatry, Wroclaw}

Medical University, Poland

A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;

D – writing the article; E – critical revision of the article; F – final approval of article; G – other

Abstract

The article reviews current literature on the biological role of carnosine, its properties and use as a supplement in periods of intense physical activity. Studies carried out on laboratory animals and humans have shown that carno-sine can have a beneficial influence on the organism. Carnocarno-sine is found naturally mainly in the skeletal muscles, central nervous system, olfactory neurons and in the lens of the eye in some vertebrates, including humans. Due to its antioxidant, protective, chelating, anti-glycation activity, this dipeptide can be used to prevent and treat diseases such as diabetes, neurodegenerative diseases, diseases of the sense organs and cancers. It may also cure or alleviate many other disorders thanks to its wide spectrum of activity. Carnosine is already used by athletes to achieve better results, due to its buffering feature, which contributes to the maintenance of the acid-base balance in the muscles. Future studies on the influence of carnosine on the human organism may lead to the therapeutic use of this dipeptide for many diseases, in addition to improving both amateur and professional athletes’ results (Adv Clin Exp Med 2013, 22, 5, 739–744).

Key words: carnosine, antioxidant effect, dementia, somatic diseases,dietary supplementation.

Streszczenie

Praca zawiera przegląd aktualnego piśmiennictwa dotyczącego biologicznej roli karnozyny, jej właściwości oraz zastosowania jako suplementu w aktywności fizycznej. W badaniach przeprowadzonych na zwierzętach ekspery-mentalnych oraz ludziach wykazano dobroczynny wpływ karnozyny na organizm. Karnozyna występuje naturalnie, głównie w mięśniach szkieletowych, ośrodkowym układzie nerwowym, neuronach węchowych, a nawet w soczew-ce oka u niektórych kręgowców, w tym u ludzi. Ze względu na swoje antyoksydacyjne, ochronne, chelatująsoczew-ce oraz antyglikacyjne działanie dipeptyd ten może zostać wykorzystany do zapobiegania i leczenia chorób, takich jak np. cukrzyca, choroby neurodegeneracyjne, choroby narządów zmysłu, nowotwory oraz wiele innych. Karnozyna jest już wykorzystywana przez sportowców w celu uzyskiwania lepszych wyników, co może zostać osiągnięte dzięki jej właściwościom buforującym, pozwalającym na utrzymanie równowagi kwasowo-zasadowej w mięśniach. Dalsze badania nad wpływem karnozyny na ludzki organizm mogą spowodować, że stanie się ona, poza naturalnym ele-mentem poprawy wydolności w sporcie, czynnikiem terapeutycznym w przypadku wielu chorób (Adv Clin Exp Med 2013, 22, 5, 739–744).

Słowa kluczowe: karnozyna, działanie antyoksydacyjne, otępienie, choroby somatyczne, suplementacja diety.

Adv Clin Exp Med 2013, 22, 5, 739–744 ISSN 1899–5276

REvIEWS

© Copyright by Wroclaw Medical University

Carnosine is an endogenous dipeptide, com-posed of β-alanine and L-histidine. This dipeptide occurs naturally in some species of vertebrates, in-cluding humans. The biggest concentration is ob-served in skeletal muscle tissue, the stomach, the

carnosine concentration with age) and diet (organ-isms on a vegetarian diet have a lower concentra-tion of carnosine in the skeletal muscles) [4, 5]. In addition, researchers suggest that synthesis of car-nosine in muscles is dependent on the availabil-ity of the amino acid alanine in the body [3, 6]. Carnosine contributes as much as 0.2–0.5% to the net weight of some muscles [7]. In animals, such factors as trauma, shock, starvation or injection negatively affect the level of carnosine in muscle tissue. Infection and trauma may be associated with cellular calcium dysregulation and myocardi-al depression. Carnosine administration may myocardi-also have a role in the contractility of cardiac cells and the regulation of intracellular calcium [2]. Despite the fact that carnosine was isolated from biological material by v. Gulevich as early as 1900, its full po-tential has not yet been discovered [7].

Antioxidant Activity

When provided to humans as a supplement, carnosine has antioxidant properties, acting against free radicals, which are factors contrib-uting to the aging of the human system. Carno-sine scavenges both reactive oxygen and nitrogen, which contain unpaired electrons, and also creates complex chemical compounds with zinc and cop-per ions [8, 9]. Carnosine dipeptide may inhibit lipid oxidation through a combination of free rad-ical scavenging and metal chelation. It also pro-vides cells with an antioxidant system that func-tions in the cytosolic environment, where water soluble oxidation mediators are often present in high concentrations [2]. It has been proved that oral use of carnosine for a period of three months improved the overall appearance of the skin and reduced the wrinkles that appear with age [10]. In mice that underwent laboratory-accelerated aging, carnosine administration prolonged life expectan-cy and improved characteristics of their physical appearance and behavior [11].

Neuroprotective Activity

Kozan et al. found that in rats that had under-gone anaphylactic shock after intracortical peni-cillin injections, intraperitoneal administration of 500 mg/kg of carnosine before and after the pen-icillin injection reduced the incidence of invol-untary muscle contractions. In the future carno-sine may be considered as a support treatment for epilepsy and for protecting the nervous sys-tem from the effects of neurotoxins [12]. Carno-sine may help prevent neurodegenerative diseases

like Parkinson’s disease, moderating its neurolog-ical symptoms and providing antioxidants and an anti-inflammatory effect on the striatum of the brain [9, 13, 14]. In rats it shows protective activity against malondialdehyde, higher concentrations of which are observed in cases of neurodegenerative diseases [1, 15]. In mice, carnosine supplementa-tion, especially a D-carnosine, reduces damage in cases of spinal cord injury [16].

Moreover, Stvolinsky and Dobrota showed that carnosine has a protective effect on heart cells and also improves the contractility of the human heart, which can counteract ischemia [17]. The da-ta suggest that carnosine may be used in medical therapy following a stroke, due to its protective ef-fects on the nervous system and reduction of the extent of infarction and neuronal damage, protect-ing against the harmful effects of ischemia [9, 18].

Antitoxic Activity

It has been demonstrated that carnosine ad-ministered to experimental animals protects against toxic substances such as cyclophosphamide and adriamycin, which are used as cytostatic drugs in the treatment of cancers and connective tissue dis-ease and can cause many side effects [19, 20]. Car-nosine’s ability to react with deleterious aldehydes such as hydroxynonenal, malondialdehyde, acetal-dehyde and methylglyoxal may also contribute to its protective functions [9]. Carnosine can prevent the increase of liver transaminase levels in the se-rum and inhibit the activity of lipid peroxides un-der the influence of ethanol, as shown in rats [21]. The consumption of alcohol leads to a fatty liver, which is a consequence of cirrhosis; the antioxi-dant and anti-inflammatory action of carnosine may be helpful in the treatment of chronic alco-holic liver damage, while also preventing the de-velopment of a fatty liver [1, 21, 22].

People suffering from lung cancer and receiv-ing radiation therapy as part of their treatment of-ten experience side effects of this type of therapy. Carnosine supplementation in combination with x-ray radiation in these individuals moderates the unwanted effects of this therapy [8].

Effects on the Sense Organs

Vision

on a population of 50,500 people show that the use of eyedrops containing N-acetylocarnosine con-tributed to preventing the development of eye dis-eases. The application of this kind of eyedrops pre-vented cataracts and lens turbidity, which lead to blurred vision and even blindness in the elderly. These drops can also be applied in cases of glauco-ma, a disease that causes progressive and irrevers-ible damage to the optic nerve and retinal ganglion cells, and in diseases related to macular degenera-tion and eye ailments associated with age [24]. In Russia, eyedrops of 5% carnosine have been devel-oped and permitted for medical use [2].

Hearing

Zhuravskii et al. demonstrated carnosie’s abili-ty to act in a protective manner on the hearing sys-tem. In rats, intraperitoneal injections of carnosine at a dose of 200 mg/kg body weight reduced the severity of degenerative-atrophic changes in the nuclei of cells in the cochlea after strong acoustic trauma [25].

Olfaction

It is probable that carnosine may play a neurome-diator role in the sense of smell in mammals [26].

Therapeutic Action

Diabetes

Swedish studies have shown that in mice with type 2 diabetes, intraperitoneal and topical admin-istration of carnosine in quantities of 100 mg/kg body weight improves the healing of wounds, in-creases the expression of growth factors and the production of cytokines [27]. In vitro studies with human fibroblasts from derma and vascular endo-thelial cells showed that carnosine increases cell vi-ability in the presence of high glucose levels [27]. The administration of carnosine protects humans against diabetic nephropathy [1, 28]. Studies con-ducted on rats by a team of Japanese scientists showed the possibility of using L-carnosine to low-er blood glucose levels by regulating the activities of autonomic nerves [29]. Carnosine has an anti-glycation effect and inhibits secondary complica-tions associated with diabetes [9].

Cancer

In rats, L-carnosine probably inhibits splenic sympathetic nerve activity and proliferation, and the multiplication and growth of cancer cells, by

increasing so-called natural killer cells (NKcells),

which are responsible for the natural cytotoxici-ty of the organism [30]. It has been shown that in humans carnosine may inhibit the growth of glio-blastoma multiforme (GBM), a primary malignant

tumor of the brain usually located in the frontal and temporal lobes. These results may open the door to important therapeutic opportunities due to the very good tolerance of carnosine, which oc-curs naturally in the human body [31].

The Metabolic Syndrome

Italian studies carried out on obese rats treat-ed with L-carnosine and D-carnosine at a dosage of 30 mg/kg in drinking water for 24 weeks sug-gest that both L-carnosine and D-carnosine re-duce hypertension, cholesterol and triglycerides fractions in the serum, and also decrease kidney damage caused by elevated levels of glucose in the blood [32].

Other Medical Applications

Human consumption of natural products with a high carnosine content, such as chick-en soup or dishes with chickchick-en breast, can inhib-it the formation and growth of influenza virus in-fections and colds, and also help to prevent those infections [33].

Physical Activity

Carnosine has a buffering effect and regu-lates the pH of muscles, allowing them to continue working at an appropriate level and improves ex-citation-contraction coupling [5, 6]. Regular oral supplementation of β-alanine increases carnosine levels in the skeletal muscles, which results in an increase in physical activity during intense aner-obic and short-term exertion; and in some series of exercises lasting more than 60 seconds, it delays the onset of fatigue in the neuromuscular system and also raises the anerobic threshold [6]. Profes-sional sprinters have a high content of carnosine in their muscles, due to a genetic predisposition or the adaptation of the organism to this disci-pline [5]. Other studies suggest that sprint training combined with a vegetarian diet or mixed diet does not affect carnosine content in the muscles [34]. In addition, β-alanine supplementation has no effect on isometric strength levels or the time course of isometric strength for a distance of 400 m [35].

a cycloergometer showed that there is a significant correlation between carnosine content and muscle fiber type: Type IIX fibers contain higher levels of carnosine, and it has also been revealed that there is a significant correlation between the average power per kilogram of body weight and the con-tent of carnosine in muscles during efforts lasting up to 30 seconds [36]. Goto et al. “examined the ef-fects of supplementation with chicken breast meat extract (CBEX) containing carnosine and anserine on hormonal responses to resistance exercise” [37]. Group of males took carnosine and anserine oral-ly in liquid form twice daioral-ly for 30 days at a dose of 2 g without physical training. Goto et al. wrote: “Before and after the supplementation period, the subjects completed 5 sets of bilateral knee exten-sion exercises (with a 90-s rest between sets)”. The results were compared with the placebo group. It was shown that the level of free testosterone did not change in either group after 30 days of supplemen-tation. As Goto et al. stated, “The blood lactate re-sponse to exercise was attenuated after supplemen-tation in both groups […]. In the CBEX group, the plasma epinephrine and norepinephrine concen-trations after exercise were significantly lower af-ter supplementation […]. The serum growth hor-mone response to exercise was also reduced in the CBEX group after supplementation. […] No sig-nificant differences in exercise-induced strength reduction (fatigue index) were observed in the 2 groups after supplementation. in exercise-in-duced strength reduction (fatigue index) observed in the two groups after supplementation” [37].

Kendrick et al. studied the influence of 10 weeks of resistance training on carnosine con-centrations in the skeletal muscles and the effect of a β-alanine dose of 6.4 g/day to increase the work done during resistance training [38]. Participants in the control group (physically active and taking a placebo) and those in the research group (taking the daily β-alanine dose) were assessed regarding

whole body strength, muscular endurance, mus-cle mass, fat content and isokinetic force produc-tion. Only the research group showed an increase in carnosine levels, but there were no significant differences in the parameters studied [38]. How-ever, it has been observed that a 12-week course of β-alanine supplementation in a dose of 3.2 g dai-ly improves exercise capacity in healthy older peo-ple, based on time of exhaustion in a constant-load submaximal test and in an incremental test, and that it increases carnosine levels in the gastrocne-mius muscle [39]. Jagim et al. conducted a study on the effects of β-alanine supplementation (an oral dose of 4 g in the first week and of 6 g in the next four weeks) on a group of wrestlers, rugby players and people who do resistance training rec-reationally [40]. The study measured lactate levels in the blood before and after supramaximal tread-mill exercise, but there were no significant differ-ences between the placebo group and the research group [40].

Conclusions

Due to its broad spectrum of activity, carno-sine may be regarded as a therapeutic factor in the treatment of many disorders and may also be used by athletes who want to improve their performance. This dipeptide shows antioxidant activity (protec-tion from free radicals), has buffering effects (help-ing to maintain the acid-base balance), chelat(help-ing effects (reducing the toxicity of metals), anti-gly-cation effects, and protects against some neurotox-ic substances. To establish appropriate daily dos-es and the duration of carnosine supplementation, it is necessary to identify any side effects and the mechanisms of its action, which requires long-term research carried out on each age group, including participants who lead physically active lives as well as those with a sedentary lifestyle.

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