Vol 88, No 3 (2023)

Tryptophan hydroxylase-2 is a key enzyme in the synthesis of the neurotransmitter serotonin, which plays an important role in the mechanisms of regulation of a wide range of physiological functions and behaviors. In this work, we studied the effect of acute ethanol administration on the expression of the c-fos early response gene and the metabolism of serotonin and catecholamines in the brain structures of B6-1473C and B6-1473G congenic mice, which differ in the C1473G single-nucleotide substitution in the Tph2 gene and enzyme activity. Acute alcoholization led to a significant increase in c-fos gene expression in the frontal cortex and striatum of B6-1473G mice and the hippocampus of B6-1473C mice. The introduction of ethanol caused a decrease in the index of serotonin metabolism in the nucleus accumbens in B6-1473C mice, as well as in the hippocampus and striatum of B6-1473G mice. Also, ethanol led to a decrease in the level of norepinephrine in the hypothalamus in B6-1473C mice. Thus, the C1473G polymorphism in the Tph2 gene has a significant effect on changes in the c-fos gene expression pattern and metabolism of biogenic amines in the brain induced by acute ethanol administration.

Proteasomes are highly conserved multienzyme complexes responsible for the proteolytic degradation of short-lived, regulatory, misfolded, and damaged proteins. They play an important role in the processes of brain plasticity, and the decrease in their function is accompanied by the development of neurodegenerative pathology. Studies performed in different laboratories both on cultured mammalian and human cells and on preparations of the rat and rabbit brain cortex revealed a large number of proteasome-associated proteins. Since the identified proteins belong to certain metabolic pathways, multiple enrichment of the proteasome fraction with these proteins indicates their important role the proteasome functioning. Extrapolation of the experimental data, obtained on various biological objects, to the human brain, suggests that proteasome-associated proteins account for at least 28% of the human brain proteome. The proteasome interactome of the brain contains a large number of proteins involved in the assembly of these supramolecular complexes, regulation of their functioning, and intracellular localization, which can be changed at different conditions (for example, during oxidative stress) or in different phases of the cell cycle. In the context of the molecular functions of the Gene Ontology (GO) Pathways, the proteins of the proteasome interactome mediate cross-talk between components of more than 30 metabolic pathways annotated in terms of GO. The main result of these interactions is the binding of adenine and guanine nucleotides, crucial for realization of the nucleotide-dependent functions of the 26S and 20S proteasomes. Since the development of neurodegenerative pathology is often associated with a regioselective decrease in the functional activity of proteasomes, a positive therapeutic effect will obviously be provided by factors increasing the proteasomal activity. In any case, the pharmacological regulation of brain proteasomes seems to be realized through changes in the composition and/or activity of proteins associated with proteasomes (deubiquitinase, PKA, CaMKIIα, etc.).

Status epilepticus (SE) triggers many pathological changes in the nervous system that are not yet fully understood and may lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in a rat model of lithium-pilocarpine temporal lobe epilepsy. Studies were performed 1 day (acute phase of the model), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. Using real-time PCR, we found that in the latent phase there is a decrease in gene expression of GluA1 and GluA2 AMPA receptor subunits, which may also be accompanied by an increased proportion of calcium-permeable AMPA receptors, which play an essential role in the pathogenesis of many CNS diseases. In acute brain slices we found a decrease in the efficiency of excitatory synaptic neurotransmission in all phases of the model when recording field responses in the CA1 region of the hippocampus in response to stimulation of Schaffer collaterals by electric currents of different intensities. However, in the chronic phase we found an increase in the frequency of spontaneous excitatory postsynaptic potentials, indicating an increased background activity of the glutamatergic system in epilepsy. This is also supported by a decrease in the threshold of hind limb extension in the test of maximal electroshock seizure in rats with temporal lobe epilepsy compared to control animals. The results obtained indicate the presence of a number of functional alterations in the glutamatergic system related to epilepsy. These findings can be used to develop antiepileptogenic therapy.

Currently, the approaches used to treat stroke have significant limitations, and neuroprotective therapy is ineffective. In this regard, the search for effective neuroprotectors and the development of new neuroprotective strategies in cerebral ischemia are still relevant. Insulin and insulin-like growth factor-1 (IGF-1) play a key role in the functioning of the brain, are involved in the regulation of growth, differentiation and survival of neurons, neuronal plasticity, food intake, control peripheral metabolism and endocrine functions. They have a complex effect on the brain, including neuroprotective effects in cerebral ischemia and stroke. Experiments on animals and cell cultures have shown that insulin and IGF-1 under hypoxic conditions improve energy metabolism in neurons and glial cells, have a positive effect on blood microcirculation in the brain, restore nerve cell functions and neurotransmission processes, and have anti-inflammatory and antiapoptotic effects on brain cells. Of greatest interest to the clinic is the intranasal route of administration of insulin and IGF-1, since it allows dosed delivery of these hormones directly to the brain, bypassing the blood-brain barrier. Intranasally administered insulin demonstrates a pronounced positive effect in the correction of cognitive impairment in elderly people with neurodegenerative and metabolic disorders. Insulin and IGF-1 administered intranasally improve increase the survival of animals with ischemic stroke. The review discusses literature data and the results of our own studies on the mechanisms of the neuroprotective action of intranasally administered insulin and IGF-1 in cerebral ischemia and the prospects for their use to normalize CNS functions and reduce neurodegenerative changes in this pathology.

Chronic alcohol consumption is characterized by disturbances of neuroplasticity. Brain-derived neurotrophic factor (BDNF) may mechanistically participate in this process. Here we aimed to review actual experimental and clinical data related to BDNF involvement in neuroplasticity in the context of alcohol dependence. As shown in experiments on the rodents alcohol consumption is accompanied brain region-specific changes of BDNF expression and by structural and behavioral impairments. BDNF reverses aberrant neuroplasticity during alcohol intoxication. According to clinical data indices characterized BDNF demonstrate close relationship with consequences of alcohol dependence. Polymorphism rs6265 within BDNF gene interacts with macrostructural changes in the brain, while peripheral BDNF concentration may reflect anxiety, depression and cognitive decline. Thus, BDNF is involved in mechanisms of alcohol-related aberrant neuroplasticity, while polymorphisms within BDNF gene and peripheral BDNF concentration may be biomarkers, diagnostic or prognostic factors in clinics of alcoholism.