Vol 41, No 3 (2024)

Nowadays, the phenomenon insulin resistance (IR) has expanded and include not only peripheral, but also central IR. However, the underlying mechanisms and physiological manifestations in the central nervous system differ from those on the periphery, and currently the concept of central IR has undergone significant changes. There are abundant evidences of the development of the nervous tissue weakened response to insulin, which directly or indirectly mediates the etiology and pathogenesis of many neurological disorders. Some molecular mechanisms underlying the decrease in the sensitivity of neurons and glial cells to insulin entering from the bloodstream to the central nervous system have been deciphered. This review is devoted to the analysis of the brain IR mechanisms in mental disorders, ischemic and traumatic brain injuries, anesthesia and postoperative stress, as well as cognitive deficits, including those associated with Alzheimer’s disease. Approaches to the diagnosis and treatment of pathological brain conditions caused by central IR are also discussed.

The previously identified ability of the anti-apoptotic protein Bcl-xL to increase expression in the hippocampus in response to stress, which correlated with resistance to stress-induced depression (Shishkina et al., 2010; Dygalo et al., 2012), indicates the potential use of this protein as a target for reducing symptoms of depressive disorder. The aim of this work was to evaluate in rats the effect of suppression of Bcl-xL expression in the hippocampus (using a TET-ON system based on lentiviral vectors for doxycycline-controlled transgene expression) on behavior in the forced swim test. The detected decrease in the expression (determined by immunoblotting) of Bcl-xL in the hippocampus and less pronounced in the frontal cortex was accompanied by a clear depressive-like effect, manifested by a shorter latency period before the first episode of freezing and a longer duration of passive behavior. Animals that received joint administration of the vector and doxycycline also showed a significant increase in the expression of brain-derived neurotrophic factor (BDNF) protein in the hippocampus, the relative weight of the adrenal glands, and a decrease in the stress level of corticosterone in the blood plasma compared to groups that received separate administrations of these drugs. Relative adrenal weights were significantly negatively correlated with Bcl-xL expression levels in the frontal cortex. Overall, gene-directed reduction of Bcl-xL expression in the hippocampus resulted in a depressive-like response in the forced swim test in rats. This behavioral effect was accompanied by a change in the functioning of the adrenal glands, manifested by an increase in the weight of the glands and a decrease in the stress level of corticosterone in the peripheral circulation.

Due to the key role of neurotrophins in brain development and plasticity, the question of whether and how the precursor of brain-derived neurotrophic factor (proBDNF) can influence the active elimination of excess cells by apoptosis is of great importance. It is supposed that proneurotrophins selectively activate the neurotropin receptor p75, thereby inducing proapoptotic signaling pathways, while mature BDNF (matBDNF) has an antiapoptotic effect. Rationale: proBDNF and matBDNF will exhibit specific expression patterns that modify the process of apoptosis in the brain of neonatal rats under induction by glucocorticoids. Thus, the study examined the effect of the glucocorticoid dexamethasone (DEX) on the levels of mRNA of BDNF and the key protease of apoptosis caspase-3, the number of cells expressing active caspase-3, as well as the proteins proBDNF, matBDNF and the key anti-apoptotic protein BCL-xL in the hippocampus of 3–4 day old rat pups in 6 or 24 hours after DEX administration. In 6 hours, DEX induced anti-apoptotic processes, namely, it increased the levels of bdnf mRNA in the whole hippocampus, as well as the content of matBDNF and Bcl-xL proteins in the CA1-3 fields and the dentate gyrus. In this case, a temporary predominance of matBDNF expression over apoptogenic proBDNF was formed against the background of a constant number of cells expressing active caspase-3. In 24 hours, DEX provoked an increase in the expression of apoptogenic proBDNF, and its prevalence over mature neurotrophin in all fields of the hippocampus, accompanied by an increase in the number of cells, expressing active caspase-3. Moreover, we found a significant correlation between the proBDNF/matBDNF ratio and active caspase-3 in all three areas of the hippocampus. It has been shown that proBDNF has its own expression pattern—different from its mature form—in the hippocampus of neonatal rats upon DEX induction and the manifestation of its proapoptotic effect is accompanied by an increase in the proBDNF/matBDNF ratio.

This study examined the effects of administration of parachlorophenylalanine (PCPA), an inhibitor of the key enzyme serotonin synthesis, on the freezing immobility and dopamine brain system in CBA/Lac mice with a hereditary predisposition to catalepsy. Administration of PCPA (300 mg/kg/day, 3 days) did not affect the duration of cataleptic freezing. Whereas, dopamine content decreased in the hypothalamus and midbrain and increased in the striatum and nucleus accumbens of mice after PCPA treatment. The administration of the drug did not affect the levels of DOPAC and HVA (dopamine metabolites) in the all studied brain structures. In addition, a PCPA-induced increase in the mRNA level of DRD2 receptor gene in the midbrain and Comt (catechol-O-methyltransferase) gene in the hypothalamus and midbrain were found. However, no effect of PCPA on the expression of DRD1 receptor gene and Th (tyrosine hydroxylase, key enzyme dopamine synthesis) gene in the brain was found. Thus, inhibition of the key enzyme of 5-HT synthesis had a significant effect on the brain DA system of CBA/Lac mice, with the greatest changes being found in the midbrain and hypothalamus.

In our previous studies, we have found a suppressive effect of a single administration of pentylenetetrazole (PTZ) in a subconvulsive dose on cellular proliferation in the dentate gyrus. In the present work, we show that this decrease in proliferation develops after acute anxiogenic effect of PTZ and is present only in the posterior portion of the hippocampus, where a decrease in the number of neuronal NO synthase expressing cells has been also found. These changes are also accompanied by a decrease in the level of nNOS protein in the hippocampus. Taken together, these observations may indicate the possible involvement of nNOS in the suppression of cellular proliferation in the dentate gyrus of the posterior hippocampus during the development of the anxiogenic effect of PTZ.

Simple, affordable and reliable methods for assessing the status of brain structures maturation are vital for preclinical studies related to the effects of early-life stress. These methods make it possible to evaluate the effectiveness of specific therapies or the prevention of stress-related pathological changes. The morphology of astrocytes is one of the markers representing functional state of synapses and thus it is indicative of maturation state of neuronal networks. We performed the method for evaluating the morphological characteristics of astrocytes using epifluorescence microscopy and the ImageJ program. Application of the method to brain sections of rats on postnatal days 18 and 30 revealed the dynamics of morphological changes in the astrocytes of the basolateral nucleus of the amygdala during normal ontogenesis. The proposed method makes it possible to evaluate not only the density of the cell population, but also their morphological parameters associated with the degree of branching and the length of the astrocyte processes. The approach used revealed sexual dimorphism in the ontogenesis: the length of the astrocytic processes increased during maturation from juvenile to pubertal period in the basolateral nucleus of the amygdala only in female rats, but not in males.

Extracellular vesicles (EVs) have recently become an important object of study. It is assumed that through EVs in the body, intercellular communication is carried out, including the regulation of gene expression, the control of proliferation and differentiation, and much more. The important role of EV in pathology is also shown. An important practical application of EVs is their use as markers of various pathological conditions. At present, the understanding of the molecular mechanisms of action of EVs is very limited, not least due to the methodological difficulties of studying these objects. First of all, it should be noted that there is no standardized method for isolating EVs, and this is a problem for a deeper study of EVs. We tried to choose the most appropriate method for isolating EVs from blood serum. For this, EVs were isolated from blood serum using three methods, after which the protein composition of the isolated EVs was determined using mass spectrometry. Each of the methods used has its own advantages and disadvantages, which must be taken into account when planning experiments in the future.