Molecular-Cellular Targets of the Pathogenetic Action of Ethanol in the Human Brain in Ontogenesis and the Possibility of Targeted Therapy Aimed at Correcting the Effect of Pathogenic Factors

Abstract

Prenatal exposure to ethanol has an impact on angiogenesis and synaptogenesis and forma- tion of neurotransmitter receptors in the brain of the embryo and fetus. Compensatory mechanism of hypoxia in conditions of prenatal exposure to alcohol involves decrease in the perimeter of the vessel and the area of the vessel in the cross section and an increase in the number of vessels in the brain. A significant effect of prenatal exposure to ethanol on the development of synaptic structures in the developing brain of the fetus was expressed in the slowing down of the formation of synaptic contacts and in the reduction of their number in comparison with the norm. Shaping synaptic contact is one of the leading processes during which largely determine the future integrative brain capabilities. The properties of benzodi- azepine receptors in the developing brain of the human ’ s embryo and fetus under prenatal alcohol influence were characterized bya decrease in affinityand an increase in their density as compensatory adaptation of the fetal nervous system to the effects of alcohol. It is reflected on during synaptogenesis in the developing brain and can lay the basis of severe disorders in the unborn child. Alcohol abuse induces neuroadaptive alters of benzodiazepine receptor system in the brain in patients with alcoholism that can modulate GABA A R and mediation of GABA in the brain, which can cause alcohol addiction. The study of the effect of mother ’ s alcoholism on the developing fetal brain (prenatal exposure to alcohol) was carried out in the brain tissue of embryos and human fetuses at the 7 – 15 week of pregnancy in accordance with the requirements of the Ethics Committee and with the consent of patients during abortion procedures under strict medical indications. About 33 embryos and fetuses were obtained from female, suffering from alcoholism and constituted the main study group. The age of women who suffered from alcoholism was 26 – 39 years old, and the duration of the disease was from 3 to 13 years. In all cases, according to ICD-10 criteria, alcoholism of grade II was diagnosed (ICD-10 F10.201, F10.202). The diagnosis of alcoholism was established in the Department of Addictive Conditions, the Institute of Mental Health, Tomsk National Scientific Medical Center Russian Academy of Science (RASci). The control group included samples of the brain tissue of embryos and fetuses obtained from healthy women who do not have a history of neurological or mental diseases comparable in age. Exclusion criteria were cases of adverse effects on brain development of embryos, namely exposure to radiation, chemicals, certain pharmacological agents and maternal diseases during pregnancy: influenza, rubella, toxoplasmosis and others. Ultrastructure of synaptic contacts and vessels of the brain tissue from embryonic and fetal brain were examined under JEM-100B and JEM-100CX electron microscopes. Electron microscopy studies addressed the intermediate layer of the wall of the forebrain, which is an accumulation of neuroblast and glioblast (including microglial cells), between which blood vessels start to grow. Morphometric analysis was performed using photographic prints from 6 to 9 cm negatives obtained from the electron microscopes. Some negatives were digitized with the scanner without intermediate paper prints. Scion Image for Windows, developed at the National Institutes of Health by Scion Corporation, was used to assess the areas of presynaptic receptors in different human mature brain of the alcoholics were performed using autopsy material (postmortem) obtained as a result of an urgent autopsy. Samples of autopsy material of the human brain were obtained during urgent autopsy (no later than 6 hours after the onset of death). Samples of the tissue of the prefrontal cerebral cortex, the cerebellar cortex and the head of the caudate nucleus of the brain in persons who were chronically subjected to alcoholization (based on anamnesis) and control subjects were postmortem. Samples of the brain were frozen and stored in thermoses with liquid nitrogen. A total of 126 samples from different areas of the human brain were obtained for the study of radio-receptor binding, including the basic group and the reference control group. In addition to the data of the anamnesis, the objective biological criteria for chronic alcoholization of man (fatty liver, cirrhosis, etc.) were used to form the main group. The control group included patients who did not have neurological and mental illnesses. Autopsy material was obtained only from males, and the age range was 33 – 54 years. Alcoholic patients were under the supervision by psychiatrists of Mental Health Research Institute and had a diagnosis according to ICD-10: F10.232; F10.302. Patients