The dissertation is dedicated to the solution of the current task of modern pathophysiology - the study of the mechanisms of the development of retina neurodegeneration with its diabetic lesion and the justification of a new path of pathogenetic correction: the use of the GABA-benzodiazepine receptor agonist carbacetam.
Justification of the choice of research topic. Among non-infectious diseases, diabetes mellitus (DM) has taken the first positions in terms of medical and social significance and has recently been considered as a pandemic of the 21st century (Ogurtsova K. et al., 2017; Saeedi P. et al., 2019). Its prevalence is more than 360 million, which will double by 2030 (Early Treatment Diabetic Retinopathy Study Research Group, 2020; Sanz-González SM et al, 2020). The most frequent cause of disability in patients with DM is ophthalmological complications, in particular, diabetic retinopathy (Sun H et al., 2022; Wong TY et al., 2020).
Ideas about the pathogenesis of DR changed as scientific knowledge accumulated. Metabolic and inflammatory theories, according to which eye damage in DM was considered as a consequence of chronic inflammation, were supplemented by recognition of the role of vascular pathology and, first of all, retinal microcirculation disorders (Kiriluk ML et al., 2019; Wang W et al., 2018). When evaluating pathological changes of the retina in DR, the primary importance of neurodegeneration processes should be recognized (Sundstrom JM et al., 2018). Metabolic, inflammatory and vascular changes of the retina in DR are important from the point of view of damage to neurons, their processes and glial cells. Regardless of other manifestations, signs of a neurodegenerative process develop in the retina - degeneration and apoptosis of neurons, astrocytes, and Müller cells, activation of neuroglia with manifestations of neuronophagy (Simó R, et al., 2018, 2019).
Gamma-aminobutyric acid (GABA) is the main inhibitory mediator in the mammalian CNS. In the retina, it is involved in signal transmission from horizontal cells to photoreceptors. Increasing the inhibitory effect of GABA leads to functional blockade and unloading of amacrine and ganglion cells (Eggers ED et al., 2020, 2023). These considerations may be the rationale for the use of GABA-ergic drugs in DR. Among the latter, the modulator of the GABA-benzodiazepine receptor complex, a β-carboline derivative - carbacetam, developed at the Institute of Physical-Organic Chemistry and Coal Chemistry of the National Academy of Sciences of Ukraine, deserves significant attention. It has been established that carbacetam exhibits pronounced antihypoxic, anxiolytic and antishock effects, due to which it can become a promising means of preventing neurogenic dysfunction of various genesis (Kmet OG et al., 2019; Ziablitsev SV et al., 2017). The known properties of carbacetam allow us to assume the possibility of its use for pathogenetically justified correction of neurochemical imbalance under conditions of diabetic retinal damage.
The purpose of the research is to study the mechanisms of the development of retinal neurodegeneration in its diabetic lesion and to justify a new direction of pathogenetic correction by using the GABA-benzodiazepine receptor agonist carbacetam.
Objectives of the study:
1. To identify the morphological signs of retinal neurodegeneration under the conditions of its diabetic damage and the effect on it of the administration of insulin and the combination of insulin with the agonist of GABA-benzodiazepine receptors carbacetam.
2. To determine the expression of a specific neuronal marker - neuron-specific enolase (NSE) and the effect on it of the introduction of insulin and the combination of insulin with the agonist of GABA-benzodiazepine receptors carbacetam.
3. To determine the expression of the marker of nerve fibers - neurofilaments (NF-H) and the effect on it of the introduction of insulin and the combination of insulin with the agonist of GABA-benzodiazepine receptors carbacetam.
4. To study the state of macroglia and apoptosis of the retina based on the expression of glial fibrillary acidic protein (GFAP) and caspase-3 and the effect on them of insulin administration and the combination of insulin with the GABA-benzodiazepine receptor agonist carbacetam.
5. To study the state of retinal microglia based on S-100 protein expression and the effect on them of insulin administration and the combination of insulin with the GABA-benzodiazepine receptor agonist carbacetam.
6. To determine the expression of the marker of pathological angiogenesis - vasculoendothelial growth factor (VEGF) and the marker of hypoxia - hypoxia-inducible factor-1α (HIF-1α) and the effect on them of the introduction of insulin and the combination of insulin with the agonist of GABA-benzodiazepine receptors carbacetam.
