Light and electron microscopy were used to study the characteristics of the formation of brain vascular structures at the early stages of development in conditions of maternal alcoholization during pregnancy. Computer morphometric methods using the Scion Image system for image analysis showed that fetuses at 11-12 weeks of development in conditions of prenatal alcohol exposure showed a decrease in the mean absolute cross-sectional area of vessels in the intermediate layer of the brain, with an increase in their relative area and an increase per unit area of sections, as compared with the control group. Vessels started to differentiate into arteries and veins from 10 weeks of development.
Chronic alcohol intake induces neuroadaptive changes in benzodiazepine receptors modulating GABAA receptors that promote alcohol addiction. Analysis of benzodiazepine receptors in the brain of Wistar rats differing by alcohol preference has demonstrated that affinity of [(3)H]flunitrazepam and [(3)H]Ro5-4864 binding with membrane fraction was reduced, while the density of specific binding sites in the brain cortex of heavy drinking and low drinking rats was increased in comparison with rats nonpreferring alcohol. Administration of anticonvulsant meta-chlorobenzhydryl urea increased affinity of benzodiazepine receptors in the brain cortex of heavy drinking rats, which improved GABA neurotransmission in the brain of these animals and reduced alcohol consumption.
Prenatal exposure to ethanol has an impact on angiogenesis and synaptogenesis and formation 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 benzodiazepine receptors in the developing brain of the human's embryo and fetus under prenatal alcohol influence were characterized by a decrease in affinity and 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.
Objective: studies of anticonvulsants have a stimulating effect on neuronal receptors; in particular GABA A / benzodiazepine receptor complex (GABA A /BzDR) can be the basis for the development of new approaches to the treatment of alcohol withdrawal syndrome (AWS) and alcohol addiction. Benzodiazepine receptors (BzDRs) of the cerebral cortex of Wistar male rats with a different preference for alcohol and BzDRs in the brain "heavy drinkers" rats, treated with original anticonvulsant meta-chloro-benzhydryl urea (m-ch-BHU) were examined in these study. Materials and methods:Wistar male rats (n=250) were used in an experimental model of alcoholism. Properties of the BzDRs of the "central" (synaptic) and "peripheral" (mitochondrial) type were examined in membrane fractions obtained from the cerebral cortex of rats under various experimental groups using radio receptor binding assays (RRA) selective ligands: Results: our study has shown that the binding affinity of [ 3 H] flunitrazepam and [ 3 H] Ro5-4864 with synaptosomal and mitochondrial membranes was decreased, but capacity of receptors was increased in the cerebral cortex of rats prefer alcohol. Administration of m-ch-BHU increased affinity of BzDRs in the cortex of "heavy drinkers" rats that can enhance the mediation of GABA in the brain of these animals. Conclusion:Our data showed that m-ch-BHU has a stimulating effect on GABA A /BzDRs in the brains of "heavy drinkers" rats and may provide a new pharmacotherapeutic approach to the treatment of alcohol addiction.
IntroductionThe development of original drugs - new generation GABAA receptor modulators (GABAAR), with an anti-alcohol orientation, non-addictive and stimulating detoxification processes, makes it possible to increase the effectiveness of therapy and reduce the cost of treatment.ObjectivesStudy the mechanism of interaction between m-Cl-BHU and GABAA - receptorMethodsMolecular docking was performed to study the molecular docking of m-Cl-BHU with at the binding site of the target protein GABAAR.Radioreceptor studies were carried out using [3H] flunitrazepam binding with synaptosomal receptors in the cerebral cortex of Wistar rats in experimental alcoholism under the influence of therapy with m-CL-BHU. Kinetic parameters (T1/2, Clt, MRT, MET, AUC) of a model substrate - antipyrine were determined in the saliva of healthy volunteers and alcoholic patients.Results IResults of molecular docking (Schrödinger program (Glide) showed: m-CL-BHU (meta-chlorobenzhydryl urea) is complementary to the benzodiazepine GABAAR. Binding energy is low) (scoring (GScore) -11.14 kKal/mol); m-CL-BHU interacts with key amino acids at the α1γ2 interface: Tyr159, Tyr209, H101 Phe77 and is characterized by a high degree of model fit - dG insert: 0.741 Binding of [3H] flunitrazepam to the benzodiazepine site of GABAAR in rat brain in experimental alcoholism, who received 14 days of m-CL-BHU at 100 mg/kg /day, increased in receptor affinity. Changes in the kinetic parameters (T1/2, Clt, MRT, MET, AUC) of a model substrate - antipyrine in the saliva of healthy volunteers and alcoholic patients using Galodif (m-CL-BHU) at 300 mg/day 21 daysConclusionsm-CL-BHU - GABAA receptor modulator with an alternative mechanism of actionDisclosureNo significant relationships.
ObjectiveChronic exposure to alcohol causes neuroadaptive changes in the brain, which leads to the recurrence of the disease. Promising in this area is to find new safe and effective pharmacological agents acting on molecular targets of influence of alcohol in the CNS.MethodsExperiments were performed on male rats Wistar and male mice (CBAxC57Bl/6)F1.U. Experimental animals were formed alcohol dependence, based on long-term use of alcohol solution. Animals in a state of alcohol dependence were injected original anticonvulsant meta-chloro-benzhydryl-urea. We evaluated parameters orienting-exploratory behavior and emotional reactivity of the animals in the test “open field”, the cellular and humoral immune response. Properties of benzodiazepine receptors of the brain examined radioreceptor method using selective ligands [3H]flunitrazepam and [3H]Ro5-4864.ResultsChronic exposure to ethanol resulted in a significant change in the parameters of the experimental animal behavior and emotional reactivity in the test “open field”, observed suppression of immune response (∼40%), and increase in the number of receptors on 54.8–59.4% associated with reduced receptor affinity. Administration of meta-chloro-benzhydryl-urea led to the abandonment of the use of ethanol, recorded a correction of the above immunological and behavioral disorders due to alcohol intoxication. Properties of benzodiazepine receptors in the brain of experimental animals receiving the drug at a dose of 100 mg/kg for 14 days, indicators affinity and receptor density were close to the values in the control group.ConclusionsAnticonvulsant has a modulating effect on the functional activity of the nervous and immune systems, reduces compulsive craving for alcohol.Disclosure of interestThe authors have not supplied their declaration of competing interest.
Objectives. Structural changes of the inner nuclear and ganglion cell layers of the retina in white mongrel male rats (n = 60) were studied with the combined effects of ionizing radiation at a dose of 5, 10, 15 Gr and light (3500 Lux, 48 h). Results. The study showed that the reactions of neurons of the inner nuclear and ganglionic layers after the X-ray and combined layers depended on the dose, such changes as vacuolization and destruction of organelles occurred and are most pronounced when combined with ionizing radiation at a dose of 15 Gr and light. An analysis of the number of hyperchromic neurons of the internal nuclear and ganglionic layers showed that after the end of exposure to ionizing radiation at doses of 10, 15 Gr, the amount of hyperchromic cells was much larger than the control values (p <0.05). After the end of the combined irradiation of ionizing radiation at a dose of 10, 15 Gr and high-intensity light, this index decreased, that indicated the failure of compensatory and adaptive mechanisms with an increase in the radiation dose and the intensification of the destruction processes.
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