Lens brightening

Cataracts are the most common cause of vision loss, especially in the elderly. Many doctors consider this disease to be as much a companion of old age as wrinkles or muscle atrophy. Usually, having discovered its signs, the doctor advises the patient to wait until the cataract matures, that is, the lens becomes completely cloudy, and the patient stops seeing with the eye, and only then sends him for an operation to replace the lens with an artificial lens.

Isn't it strange? For example, we usually first try to heal teeth and only then insert artificial ones. Why not interfere with the development of cataracts in the early stages and try to at least slow it down, if not prevent it? However, this is not easy to do. First, the very early stages are difficult to identify. The transparency of the lens decreases slowly, and the person himself does not immediately notice it. Visual impairment is often attributed to other causes. And ophthalmologists, during examinations, usually diagnose cataracts using a slit lamp, which allows them to detect only pronounced opacity.

Anyone who has ever seen a bright beam of light in a dark room, for example, from a projector in a cinema, will understand the principle of operation of a slit lamp. All the dust particles that scatter the light are visible in the beam. The ophthalmologist also directs the beam from the lamp through the vertical slit into the pupil of the eye and, looking at the side of the lens, evaluates its opacity. This assessment is largely subjective, and if obvious opacities are visible, then an inexperienced doctor may not notice slight initial changes. Indeed, is any of us able to assess the degree of dustiness in the air in a room? 

The second reason is more significant. Until recently, it was not clear what molecular processes lead to lens opacity, but without this, it is impossible to develop more advanced methods of treatment. And therefore, it is useless to engage in diagnostics.

The lens is not a lens made of a homogeneous substance, but an organ made of cells. Those at the equator retain a core and divide throughout their lives. In them, as in the cells of the bone marrow and intestinal epithelium, until the last days, the telomerase enzyme is active, which completes the end sections of chromosomes and allows cells to divide almost indefinitely.

After division, cells deposited in the thickness of the lens move to its posterior pole, lose nuclei, stretch out and turn into fibers. As a result, the living magnifying glass grows larger over the years. Zoologists know that the most accurate age of a rodent can be determined by the weight of its lens.

The lens fibers form many gap junctions — special channels that connect them into syncytium, that is, into a supercell with general metabolism. In this way, the lens is like a heart. However, most fibers lack a nucleus and many organelles such as mitochondria. They are energized (i.e., ATP) by epithelial cells located at the periphery of the lens.

Proteins-crystallins are formed in the fibers, which are not renewed from the moment of their synthesis until the very death of the organism. One can only be surprised that they serve well for decades without failing. And yet, in old age, and sometimes with illnesses and injuries, the lens becomes "more turbid than standing water." The immediate reason for this is the degradation of crystallins. With age, they change chemically and are assembled into aggregates. Perhaps this occurs on cell membranes, where particles are formed that scatter light. Most likely, chemical changes in protein molecules at some point lead to the fact that their natural packing is disrupted, internal hydrophobic groups look outward, and then proteins easily adhere to membranes. This is only a hypothesis so far, but very plausible.

But what acts on proteins? The origin of cataracts has been debated for decades, with various changes in the chemistry of the lens. It is known, for example, that with the development of senile cataracts, more sodium and less potassium become in the lens, which disrupts the water balance, which contributes to an increase in the content of monosaccharides in the blood (often cataracts develop as a result of diabetes). However, such observations were sketchy.

Much became clear in the late 1980s, when they started working on lens cell membranes. By this time, it was already known about free radical processes and their role in the normal life of cells and the development of various pathologies. Recall that free radicals are chemically active particles with unpaired electrons, which are formed in some oxidation processes (mainly in the mitochondria of cells). They start a chain of reactions, often leading to disruption of membrane phospholipids, proteins, nucleic acids, and other cell components. At the same time, the destruction of membranes (in muscles, for example) cannot be regarded as an absolute evil: it is necessary for the renewal of tissues under increased loads and is useful to some extent.

The study of membranes and free radical processes in them directed the efforts of specialists in a new way. In 1991, in the Belgian city of Ghent, within the framework of a program for the study of aging in Europe, a symposium "Lens membranes and aging" was held. One of the organizers of this symposium, G. Vrensen, noted: “The membranes of the lens fibers play a decisive role in the development and maintenance of high ordering of the lens structures. There are good reasons to believe that membrane disorders are the main causes of cataract development." 

The basis of the membranes in lens cells, like in other cells, is a double phospholipid layer. It is very sensitive to the action of reactive oxygen species, which cause chain processes of free radical oxidation. Graduates of the Department of Biophysics of the 2nd Moscow Medical Institute (now the Russian State Medical University) M. Babizhaev and A. Deev, having studied the stage-by-stage dynamics of cataract development, proved that lipid peroxidation plays a leading role in its development. Before them, scientists compared normal lenses, in which there was still no significant oxidation, with lenses at the final stages of cataract development, where everything was already oxidized and oxidation products were degraded. The works of Russian scientists were included in the top ten most significant in the pathogenesis of cataracts in 1985–1990, based on which the American National Institute of Health has formed a new research program. Almost all experts now agree that free radical oxidation of membranes plays a key role in lens clouding. This is what it consists of.

Free radicals enter the fibers of the lens, probably from epithelial cells that actively breathe (i.e. oxidize). In addition, kynurenine pigments that absorb ultraviolet light in the A-band when interacting with oxygen can generate singlet oxygen, which has an increased reactivity. In some pathologies, lipid peroxides, which are also very active, can diffuse into the lens from easily oxidized phospholipids of the retina.

In the lens, free radicals and lipid peroxides attack membrane phospholipids. Those are oxidized and, in turn, also generate lipoperoxides, as well as aldehydes, no less dangerous for the cell. At the same time, the barrier function of membranes is disrupted, which normally does not allow ions to freely pass into the cell, and from it outward. As long as the membrane is intact, it regulates the movement of ions, so that an electrical potential is formed on opposite sides of it. When the membrane deteriorates, the membrane potential of cells decreases, and their energy is inhibited, which is necessary to maintain the normal structure of cells, and the transparency of the lens depends on it. In addition, although the membranes account for no more than 5 % of the volume of the lens, their contribution to light scattering reaches half. When the ordering of membranes is disrupted, bubbles and crimped formations form in them, which scatter light even more.  

Oxidation in the lens, as in other organs, is inhibited by antioxidant systems — substances and enzymes that neutralize free radicals. Antioxidants work together in a living cell. In different tissues, their number and ratio are different, because the metabolism in them is not the same.

The most important antioxidants are glutathione and enzymes dependent on it. The content of glutathione in the epithelium of the lens is more than ten times higher than that in the cells of other mammalian tissues. The liquid that washes the lens (aqueous humor) contains another antioxidant — ascorbic acid, and there is about twenty times more of it than in the blood.

About twenty years ago, researchers have paid attention to yet another antioxidant - dipeptide carnosine (from the Latin caron, carnis — meat). This mysterious compound was discovered in 1900 by our compatriot V. Gulevich, who isolated it from beef. All his life, his student, the patriarch of Soviet biochemistry, Academician S. Severin, was engaged in the study of an unusual substance, and many other scientists also paid tribute to him. It was clear that this is a very important compound, but its function and mechanism of action were unknown for a long time. In the early 80s, at the Department of Biochemistry of Moscow State University, which was headed by S. Severin, it was suggested that carnosine protects membranes (in particular, mitochondrial membranes) from oxidative stress, and by the end of the decade, it was proven in leading laboratories of the world. In 2000, the discovery of carnosine was 100 years old, and in commemoration of this anniversary, the editorial staff of the journal "Biochemistry" devoted a whole issue (v. 61, No. 7) to the study of the compound.     

Carnosine is a water-soluble antioxidant that primarily neutralizes OH-radicals, singlet oxygen, and lipid peroxides. It is found mainly in excitable tissues. But it probably also plays a significant role in maintaining the normal functioning of the lens. Interestingly, birds have a compound similar to carnosine. It is called anserine (from the Latin anser — goose). Other carnosine derivatives have been found in marine mammals and snakes. 

There is a lot of carnosine in the eyes of birds, but cataracts are rarely found in them. And this is even though many of them make long flights at high altitudes, where ultraviolet light is so bright, and waterfowl look at the surface of the water for a long time, which reflects it well (it is known that ultraviolet light is one of the main factors in the development of cataracts).

The high content of carnosine in the eyes of birds was first noticed by L. Broude, another student of V. Gulevich. From here, it was not far from the idea — to protect the lens from clouding with dipeptides — antioxidants. With older dogs, this was successful — they began to see much better after instilling the carnosine solution in the eyes. However, it is not so easy to introduce carnosine into the human lens. If its solution is dripped into the eye, then in the aqueous humor, on the way from the cornea to the lens, it will be destroyed by the enzyme carnosinase. In this case, histidine is formed, which is easily converted into histamine — a mediator of allergic reactions, which, when introduced from the outside, has the same effect as an allergen.  

The Russian scientist M. Babizhaev, together with foreign colleagues, decided to "cheat" carnosinase, keeping the active principle of the drug. For this, a synthetic preparation was created, similar to a natural substance, but the group by which carnosinase recognizes carnosine was masked: an acetyl group was hung on the N- end of the peptide (the amine group of beta-alanine). The drug is not destroyed by carnosinases, penetrates the cells of the lens, turns into carnosine, and, acting as an antioxidant, protects the lens from clouding. Several of these pseudodipeptides have received international and Russian patents. 

One of the carnosine derivatives was tested in rats that developed cataracts due to diabetes. These works were carried out at Monaco and the University of Nice in France. The drug was effective when added to the water that rats drank. It shouldn't be broken down in the digestive tract and the blood, so it can be taken orally without fear of losing activity.

So, there seems to be a cure for cataracts. What are its capabilities? Of course, if the process has gone too far (vision is less than 0.3), acetyl carnosine will help no more than a magic session. However, in the early stages, it works: the lens becomes less cloudy and further cloudiness slows down (of course, for this the drug must be used regularly). However, the transparency of the lens also changes from physiological reasons: it temporarily worsens with severe general fatigue.

A device based on the glare effect (from the English glare — radiance, halo) will help to detect the onset of the pathological process. When the eye is illuminated with a small light source and the lens is transparent, the object next to that source is visible. If the lens is cloudy, the halo from the lamp prevents it from being noticed. Glair testing of the population would allow timely identification of people in whom the transparency of the lens decreases too quickly with age. Such people should be offered means to slow down the development of cataracts. However, they should not forget the usual methods of prevention: good nutrition, including sufficient protein and antioxidants.

If the history of carnosine and its derivatives in cataract prevention had a happy end (registration, production, and sale of the drug), this article would not need to write a small addition. The fact is that in our country no one is interested in the drug so much as to conduct clinical trials and establish production.

Much has been done in the West. N-acetyl carnosine (NACA) was tested in the clinic by the specialists of the American company Innovative Vision Products. The results, published in international journals, showed the effectiveness of the drug and served as the basis for the release of a kind of eye supplement "Can-C" (the name is consonant with can see — I can see), which is sold on the Internet orders by the international company International Anti - Aging Systems (IAS). Plenary reports on the history of creation, the possible mechanism of action, and the effectiveness of the drug in gerontology and ophthalmology were made by M. Babizhaev at international conferences in Monaco in 2002 and 2003. The development of nonsurgical cataract treatment entered the American Commercialization Institute. Since 2003, the drug began to be sold in the United States under the commercial name "OcuZyme" under a very curious condition: if it does not help within three months, the patient is refunded the money for the course of treatment. According to the American geronto-ophthalmologist Richard Cohen, the drug is useful not only in the initial stages of cataracts but also in case of presbyopia (a decrease in the volume of accommodation due to a decrease in the elasticity of the lens), glaucoma, dry eye syndrome, diabetic retinopathy.  

 

Based on the article by M. Rachkovsky "Lightening the lens" published in the journal "Chemistry and Life" (2003, No. 9).

 

 

 

 

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