Oxidative Damage of Proteins Precedes Loss of Cholinergic Phenotype in the Septal Neurons of Olfactory Bulbectomized Mice.

BACKGROUND: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer's disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer's disease. OBJECTIVE: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. METHODS: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. RESULTS: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. CONCLUSION: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer's disease.

[The prospects of using the technology of genome editing for correction of neurodegenerative diseases.]

We reviewed the results of modern studies using gene therapy methods for correction of neurodegenerative diseases. We analyzed approaches based on the technologies of gene editing and their prospective use in medicine. We discussed some limitations associated with the features of pathogenesis of neurodegenerative diseases for application of the genome editing tools directing to for the treatment of these pathologies.

Acquisition of an active avoidance reaction in rats and morphological changes in the hippocampus in pentylenetetrazol kindling.

The relationship between measures of active avoidance behavior and morphological changes in the hippocampus was studied in rats after kindling induced by administration of pentylenetetrazol. Pentylenetetrazol kindling impaired the acquisition of the avoidance reaction and increased the number of intersignal reactions without altering the acquisition of the avoidance reaction in the shuttle box in rats. The numbers of neurons in the hippocampus (fields CA1 and CA3) and dentate fascia decreased, while the numbers of damaged neurons increased. Inverse correlations between seizure severity and the numbers of neurons in hippocampal fields CA1 and CA3 and the dentate fascia were seen in rats subjected to kindling. Rats of this group also showed positive correlations between seizure severity and the numbers of damaged neurons in field CA1 and the dentate fascia. There were no correlations between measures of convulsive activity or the number of cells in hippocampal zones and measures of the acquired avoidance behavior. Control animals showed negative correlations between the numbers of damaged cells in field CA1 and the dentate fascia and the characteristics of avoidance behavior in the first and third training sessions.

Prophylaxis of encephalopathies and risk factors of atherogenesis development in the postresuscitation period in rats by means of succinic acid.

The effect of oral administration of succinic acid was studied in 66 rats exposed to 10 min cardiac arrest with further resuscitation. A total of 30 mg/kg of the drug were administered daily for 5 days starting with day 3 up to day 7 after resuscitation. The experiments have revealed that treatment with succinic acid caused normalization of the orienting behavior in an 'open field' test, decrease of the intensity of response to electric shock, normalization of free radical formation in the brain and serum and reduced cerebral morphological changes. The succinic acid prevented the increase of cholesterol, triglyceride and low density lipoproteins in the blood. The data suggested that after additional trials the succinic acid could be used to prevent development of postresuscitation encephalopathies (3 months after reanimation).