Vol 13, No 4 (2019)

Abstract—The role of astroglia cells is more complex than the idea that they are an elastic frame that provides structural and metabolic support in the brain. The data of cyto-biochemical and physiological analysis demonstrate that astrocytes are integral elements of neural networks. Astrocytes can affect synaptic processes due to release or modulation of the activity of neurotransmitters. Here, we present ideas on an astrocyte hypothesis, which determines the role of astroglia as a specific management service. Due to the interaction of gliotransmitters with neurons, astrocytes affect the formation of neuronal networks and participate in the regulation of memory and complex behavior in the healthy or diseased brain. The role of astrocytes in organization of network spaces and formation of neuron–astrocyte domains is considered to be one of the physiological mechanisms of memory. We demonstrated the mechanism of the participation of astrocytes in synaptic disintegration and psychoneurological pathology for the first time.

Abstract—It is hypothesized that the basis of nightmares in post-traumatic stress disorder (PTSD) is modification of synaptic transmission in neural circuits that contain one of the following structures: the visual cortex, prefrontal cortex (PfC), basolateral amygdala (BLA), hippocampus, connected with them nuclei of the thalamus and basal ganglia (BG). The emergence of dreams is promoted by the induction of long-term potentiation of excitatory inputs to the striatonigral cells and the long-term depression of the inputs to the striatopallidal cells that are connected with the visual cortex, and give rise, respectively, to a direct and indirect path way through the BG. This leads to synergistic disinhibition of certain groups of neurons in the thalamus by the output BG nuclei and the formation of activity patterns that reflect dream content in the areas of the visual cortex and hippocampus, which are connected with thalamus. The occurrence of emotionally negative episodes in dreams is a consequence of an increase in BLA activity during PTSD, whose signals are summed with the signals from the hippocampus and PfC on the neurons of the ventral striatum. This mechanism suggests that, in order to prevent nightmares, it is necessary to induce long-term depression of the excitatory inputs to the neurons of the limbic structures and to the striatonigral cells. It is undesirable to act on the receptors on the striatopallidal cells because it may simultaneously induce long-term potentiation of the excitatory inputs to the neurons of PfC, BLA, and hippocampus, which have receptors of the same types. Given the data on the types of receptors on striatal neurons, it follows from the modulation rules we earlier formulated that nightmares may be prevented by antagonists of dopamine D1 receptor and alpha1 adrenoceptor and agonists of glucocorticoid, serotonin 5-HT1B, and cannabinoid CB1 receptors. The use of mineralocorticoid and serotonin 5-HT2A receptor agonists, as well as antagonists of alpha2 adrenoreceptors and dopamine D2 receptors (which are part of some antidepressants and antipsychotics) is undesirable in order to avoid side effects. The treatment should be short-term and used only at bedtime, to avoid impairments of physical activity and sensory perception in the awake state. The consequences of the proposed mechanism are consistent with the known results of clinical studies.

Abstract—In the early 2000s, it was shown that dopamine is synthesized not only by dopaminergic neurons that possess the necessary set of enzymes, tyrosine hydroxylase and aromatic L-amino acid decarboxylase (AAD), but also by non-dopaminergic (monoenzymatic) neurons containing one of the enzymes. In this case, L-3,4-dihydroxyphenylalanine (L-DOPA), which is synthesized in neurons containing tyrosine hydroxylase, is transferred to neurons containing AAD, where dopamine is synthesized. The evidence for cooperative dopamine synthesis in our previous studies was a decrease in the total dopamine synthesis during incubation of a suspension of neurons of the tuberoinfundibular system (TIS) of fetuses or TIS slices from adult rats in the presence of a neutral amino acid that is a competitive inhibitor of the membrane L-DOPA carrier. In this work, the previously applied methodological approach was improved by using only sections of TIS and 2-amino-2-norbornanecarboxylic acid, a synthetic non-metabolizable L-DOPA membrane carrier inhibitor. This made it possible to confirm the presence of cooperative dopamine synthesis in TIS in fetuses and adult rats, and to obtain additional evidence of this synthesis in the form of an increase in the intercellular content of L-DOPA during inhibition of its membrane carrier. In addition, using an improved method we quantitatively characterized the synthesis of dopamine by nondopaminergic neurons and compared it in fetuses and adult rats. It was shown that the proportion of cooperative dopamine synthesis from the total dopamine synthesis by monoenzymatic and dopaminergic neurons in TIS in rat fetuses is 1.8 times higher than in adult animals. A six-fold increase in the synthesis of dopamine by rat TIS monoenzymatic neurons from the end of the prenatal period to adulthood are of particular interest from the standpoint of the functional role of dopamine produced by monoenzymatic neurons. Thus, in ontogeny, the proportion of dopamine synthesis by nondopaminergic monoenzymatic neurons in the general synthesis of dopamine is significantly reduced and the absolute value of cooperative dopamine synthesis increases by many times.

Abstract—Elevated levels of glucocorticoids in the perinatal period of ontogeny may provoke further development of neuropathology, whose mechanisms can involve apoptosis of brain cells caused by impaired expression of neurotrophins, including the practically unstudied neurotrophic factor 3 (NT3). In order to clarify this issue, we explored the effect of glucocorticoid dexamethasone (DEX) on the NT3 and the key apoptotic protease caspase-3, mRNA levels as well as immature (proNT3) and mature (matNT3) forms of the investigated neurotrophin in the hippocampus of 3–4-day-old rats 6 or 24 hours after DEX administration. In 6 hours but not in 24 hours DEX increased the NT3 mRNA levels in the whole hippocampus, as well as the proNT3 and matNT3 proteins contents the CA1–3 fields and the dentate gyrus of the structure. In this case, the expression of apoptogenic proNT3 temporarily predominated over matNT3; however, this was not accompanied by an increase in the caspase-3 mRNA level.

Abstract—We studied the activity and some physicochemical parameters of LDH in the rat brain under normal and hypothermic conditions. It was found that during hypothermia the activity of LDH in the rat brain increases, while this increase is less pronounced in an enzyme preparation purified from ballast proteins. A study of LDH self-fluorescence showed a decrease in the intensity of total fluorescence of LDH, in which the main contribution is made by tryptophan residues. Analysis of the second derivatives of the fluorescence spectra showed that hypothermia affects tryptophanyls, which are located on the periphery of the LDH molecule. Study of the binding kinetics of the fluorescent probe ANS with LDH showed the presence of at least two types of binding sites of the probe, which differ in polarity. Hypothermia leads to a decrease in the fluorescence intensity of the ANS, a decrease in the number of binding sites, an increase in the probe dissociation constants, and a shift in the inflection position on the graph of the temperature dependence of the ANS fluorescence to higher temperatures. The study of the content of sulfhydryl and carbonyl groups in the LDH molecule suggests that one of the causes of the changes in the activity and spectral characteristics of LDH in the brain of hypothermic rats is the modification of the enzyme by reactive oxygen species.

Abstract—We studied lipid peroxidation and measured the products of lipid peroxidation (LPO) together with the indices of the antioxidant system (AOS) in the blood of patients with epilepsy of various severities in the South Kazakhstan region of Kazakhstan. We examined 95 epileptic patients, including 35 patients with 3 seizure attacks per year, 30 patients with up to 12 seizure attacks per year, and 30 patients with more than 12 seizure attacks per year, that is, low, moderate, and severe levels of epilepsy, respectively, and 30 healthy men. We measured LPO products with simultaneous estimation of activity of superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPO) as well as antiradical (ARA) and antioxidant activity (AOA) in biological fluids. We also studied non-enzymatic antioxidant indices, such as the contents of α-tocopherol and SH-groups depending on epilepsy severity. We found that the content of LPO products in red blood cells and the deficit of the mechanisms of antioxidant defense increased depending on the severity of epilepsy in patients. In parallel to the increase in the level of lipid peroxides, lipid oxidizability was also enhanced in the blood of epileptic patients. Insufficiency of α-tocopherol was associated with decreased activity of SOD, AOA, and ARA in the body of patients. This complex study indicates that in epilepsy accumulation of lipid peroxides in the blood and a decrease in the activity of the AOS in the body occur. The expression of these processes directly depends on the severity of epilepsy.

Abstract—Oxidative stress (OS) plays a significant role in the pathogenesis of Parkinson’s disease (PD) and is accompanied by the development of free radical reactions of lipid peroxidation. The growth of highly reactive products of oxidative metabolism of polyunsaturated fatty acids (PUFAs) leads to dysfunction and the subsequent death of dopaminergic neurons and contributes to the emergence and progression of PD. This paper assesses the prognostic significance of lipid peroxidation (LPO) products determined in the blood of patients with PD as possible biomarkers of various stages of the disease. The content of lipid hydroperoxides (LH), malondialdehyde (MDA), and 4-hydroxynonenals (4-HNE) was determined in the peripheral blood of 240 patients at stages 1–4 of the disease according to the Hoehn and Yahr scale. For all examined patients, regardless of the stage of the disease (stages 2–4), an increase in the level of lipid hydroperoxides by 20% was observed, on average. Elevated levels of MDA were registered in patients with a higher disease severity who were at the advanced stages of the disease (stages 3 and 4). For patients at stages 1 and 2 of the disease the content of MDA remained within normal levels. The content of 4-HNE increased in patients at stages 2, 3, and 4 of the disease proportionally to the severity of the disease. The most pronounced increase in the content of 4-HNE was detected in patients at the advanced stages of the disease (stages 3 and 4). In patients at the second, earlier stage of the disease, the value of this parameter was 34% lower than that in patients at the advanced stages. In patients at the first stage of the disease, all measured parameters of LPO were comparable to control values and therefore could not play a significant diagnostic biomarker role. An important aspect of this study is that some LPO markers (LH and 4-HNE) are associated with both early and late stages of the disease, while the content of MDA increased at the advanced stages. Therefore, MDA and 4-HNE may have a high prognostic value, reflecting the severity of the disease. The most sensitive and specific indicator of LPO is 4-HNE, since its content increases proportionally to the severity of the disease (stage 2 < stage 3 < stage 4). The results we obtained are important for the development of complex neuroprotective approaches to the treatment of this disease, which can prevent the selective death of nervous tissue in PD and delay the development of the neurodegenerative process.