IPH AVN Peptide Complex in Ophthalmology

Age-related retinal pathologies, such as age-related macular degeneration and pigmentary retinitis, pose complex challenges in clinical ophthalmology. Current treatment methods for retinal diseases, including laser therapy, surgical interventions, and medications, primarily focus on reducing the risk of further complications. It’s important to note that pathogenetic therapies for degenerative retinal diseases are scarce in global ophthalmic practice, leading to irreversible blindness in patients. Consequently, extensive research is underway to explore pathogenetic treatments, leveraging the molecular biology advancements and the effective operation of vascular peptide complexes with retinoprotective properties. These complexes work by influencing key mechanisms to achieve significant treatment outcomes. Various scientific studies in the field of cellular replacement therapy for restoring the functional activity of retinal neurons have demonstrated that vascular peptides can stimulate the expression of cell differentiation markers by binding to gene promoter regions. This is crucial for cell development, interaction, and function.

Age-related changes in ocular tissues follow the general principles of aging in the body but also have unique characteristics due to the structural and functional features of the visual system and the presence of autoregulatory mechanisms in its blood supply.

Age-related retinal pathology is largely determined by the histological structure of the retina. Presently, the physiological and biochemical mechanisms of photoactivation, responsible for perception and amplification of the primary light signal, are known. The morphological features of its layers also play a significant role. The retina is a delicate tissue layer lining the back of the eye from the inside. Histologically, the retina consists of ten layers of nerve cells interconnected morphologically and functionally. It comprises six types of neurons and one type of glial cells, forming a highly organized layered structure. The primary layer of the retina consists of light-sensitive cells, photoreceptors (rods and cones). The primary function of the retina is to convert the light signal captured by photoreceptors into an electrical impulse transmitted to the brain. Age-related dysfunction of retinal cells leads to the disruption of normal signal formation and, consequently, vision impairment.

Elderly individuals often experience decreased visual acuity and color perception, primarily attributed to the loss of retinal neurons. Among all retinal cells, photoreceptors are the most vulnerable to aging. One of the reasons for this vulnerability is oxidative stress, which results from the impact of light. Ultraviolet radiation leads to the formation of free radicals, causing oxidative damage to the cell membrane of retinal cells and initiating lipid peroxidation. All of these factors trigger involutional processes in the retinal tissues, leading to degenerative changes. Additionally, aging brings about a physiological decrease in the number of retinal neurons. Several years of observation in various animal models assessing age-related ganglion cell loss have shown that each month, all animals experience a reduction in ganglion cell count in the retina. In mice, this indicator constituted 2.4% of monthly ganglion cell loss, whereas in rats, it was lower at 1.5% of monthly loss. However, by the end of life, this indicator reached a uniform value of 35% in both animal groups. Furthermore, artificially induced retinal ischemia (lasting for 75 minutes) exacerbated the existing scenario. The number of ganglion cells decreased by 20% in the group of young animals and by 35% in the group of old rats. Consequently, the retinas of old animals proved to be more susceptible to damaging agents than those of the young. Such a reduction in ganglion cell count with age also occurs in the retinas of primates, including humans. Therefore, age-related degenerative changes in the retina result from a significant reduction in the number of retinal ganglion cells, especially under the influence of adverse factors. This explains why the number of rods and cones in individuals aged 60 and above is half that of 20-year-olds. Similarly, a decrease in the number of bipolar and ganglion cells is observed in people aged 35 to 60.

With advancing age, degenerative changes are observed in the optic nerve fibers. They are gradually replaced by connective tissue, and the inner boundary membrane thickens. Ganglion and bipolar cells accumulate lipids, while astrocytes actively express glial fibrillary acidic protein. These degenerative processes are primarily driven by disturbances in the metabolism of specific proteins in the retinal pigment epithelium and other layers of the retina.

Involutional changes in the retinal pigment epithelium layer are characterized by a significant reduction in the number of nuclei, sparse nuclear spaces, and the flattening and shortening of pigment cells. Age-related morphological changes in Bruch’s membrane include thickening, distortion, and the deposition of Sudanophilic masses and lipids. Accumulations of amyloid fibrils are found in the inner collagen layer of the membrane. In cases of involutional degeneration of the retinal pigment epithelium, undegraded neuroepithelial discs accumulate in the cytoplasm of these cells, eventually forming fibrils of pathological amyloid protein.

A correlation between the degree of subretinal deposits and age was observed in a mouse study (2, 9, and 16 months old), evaluating the quantity of subretinal drusen using scores as an assessment unit. In 16-month-old mice, this indicator was 2.5 times higher than in young animals. Additionally, a diet high in high-density lipids and ovariectomy, leading to hormonal imbalance, can provoke destructive changes in the retina. However, lipid metabolism disruption primarily occurs in organisms with a genetic predisposition, as confirmed by experimental research. The presence of the paraoxonase polymorphism gene leads to lipid metabolism disorders.

Age-related photoreceptor degeneration is accompanied by changes in the neural layers of the retina. The restructuring of retinal neural layers involves four stages. In the first stage, the outer segments of rods and cones are lost. The second stage reveals apoptosis of rods and cones, leading to the disruption of their interaction with the network of amacrine and bipolar cells. Subsequently, apoptosis of most neurons is induced. The remaining retinal cells seek sources of stimulating signals, leading to the migration of bipolar and amacrine cells toward the external and internal boundary membranes. As a result, the retina loses its layered structure and its ability to perform phototransduction. In the final stage of the disease, metabolic processes are disrupted, and neurons deprived of oxygen and nutrients undergo necrosis, being replaced by glial cells. Thus, metabolic disturbances of photoreceptor proteins, retinal pigment epithelium, and retinal neurons underlie the degenerative processes in the retina.

Vascular factors also play a significant role in the development of retinal degeneration. It is known that age-related changes in the arterial system of the eye are more pronounced than those in the venous system. With age, the number of functioning vessels decreases, especially terminal branches and anastomoses. During ophthalmoscopy, the entire vascular tree of the retina appears impoverished and pale. The natural tortuosity of arteries and veins disappears; they become straighter. The lumen of the vessels narrows uniformly along their entire length, with weak light reflexes from the vessel walls, which dull as the vessel’s caliber decreases. Fluorescein angiography data indicate significant slowing of blood flow in both the arterial and venous systems of the retina in people over 65 years of age. The avascular zone of the macular area widens, and the characteristic structure of the vascular arcade disappears. Morphological studies indicate the development of fibrosis and hyalinization of the vascular wall, thickening of the basal membrane, and collagenization of fibrils.

Involutional desquamation of the vascular endothelium, elastofibrosis, and thickening of the vessel wall due to fiber swelling and plasma infiltration lead to a narrowing of the vessel lumen. The vessels lose their flexibility, becoming dense, rigid, and losing their adaptive capabilities, including fluctuations in arterial and intraocular pressure. Anatomical and morphological degradation changes in the vascular membrane and retina, respectively, result in a decrease in the functional activity of the latter. With age, there is a significant decrease in bioelectrical activity and an increase in the duration of nerve impulses in the retina due to involutional changes. A decrease in the intensity of transcapillary metabolism in the vessels of the retina and the vascular membrane leads to the development of age-related retinal hypoxia, reducing metabolic processes and, consequently, visual functions. All of these factors contribute to the occurrence of age-related retinal hemorrhages and the development of retinal dystrophy.

With age, the spectrum of fundus autofluorescence shifts by 10–20 nm towards shorter wavelengths due to an increase in the number of fluorophores in Bruch’s membrane. Involutional changes in the retina and the vascular membrane contribute to the development of age-related retinoschisis and annular (ring) retinopathy. Retinoschisis can lead to retinal detachment with all its consequences. The course of the pathological process can be slow or very rapid, leading to scotomas and decreased visual acuity when the process affects the macular area. However, age-related changes in the retina do not always lead to macular degeneration. Nevertheless, a decrease in the body’s adaptive capabilities against the backdrop of involutional changes creates favorable conditions for the development of pathological processes in the vascular membrane and retina.

Impaired blood flow in the arterial and venous vascular channels leads to ischemic tissue changes in the retina, resulting in secondary dystrophies. The microcirculation network always responds to the effects of pathogenic factors as a unified system.