A pressing issue in medicine is the safety of assisted reproductive technologies (ART) and their impact on predisposition to various diseases. Here, we investigated for the first time the long-term effects of widely used reproductive technologies in a 5xFAD mouse model of Alzheimer’s disease (AD). The objective of this work was to study the behavioral characteristics of 5xFAD mice compared to wild-type (WT) control mice. Offspring were obtained either by natural mating or due to in vitro embryo culturing for 27 h in KSOMaa medium, followed by embryo transfer to recipient females. Once the offspring reached 6 months of age, a series of the following behavioral tests was conducted—tail suspension (TS) test, elevated plus maze (EPM) test, and open field (OF) test, as well as body weight and brain mass were measured. It can be concluded that some long-term effects of ART application may be similar in mice predisposed to AD (5xFAD genotype) and control WT mice. Such effects include increased body weight and reduced anxiety in the EPM test. However, some ART effects differed between 5xFAD and WT progeny. Specifically, this concerned the presence/absence of effects on the immobility time in the TS test and the number of grooming bouts in the OF test. The results may have translational implications for medicine.
Adolescence (10–19 years, according to WHO classification) is characterized by significant neuroendocrine remodeling, active reorganization of synaptic connections, and physiological insulin resistance. These processes create a unique metabolic environment where even transient glucose fluctuations can substantially modulate cognitive functions, a phenomenon not typically observed in adults. This review aims to provide an interdisciplinary analysis of experimental, clinical-physiological, and psychophysiological data concerning the relationship between glucose metabolism, age-related neuroendocrine regulation, and cognitive functions in adolescents. Furthermore, it seeks to identify the key mechanisms that determine the brain’s sensitivity to glycemic changes. Based on existing literature, we highlight three key findings: (1) Age-related dynamics of cerebral glucose utilization (CMRglc): CMRglc is twice the adult level at age 5 and reaches a plateau by 16–20 years. (2) Key regulatory roles: Glucose-regulated neurons in the hypothalamus and brainstem play a crucial role, alongside the modulatory effects of insulin, leptin, and GLP-1 on the prefrontal cortex (PFC) and hippocampus. (3) Impact of stable glycemia: Stable postprandial glycemia, achieved with a low glycemic load, is associated with improved working memory and sustained attention 2–3 hours after a meal. We also discuss promising research directions, including the quantitative assessment of glycemic variability thresholds, the study of how transient glucose changes affect learning, and the development of physiologically sound nutritional recommendations for adolescents facing high academic workloads.
Early-life stress has been identified as a risk factor for neuropsychiatric disorders, but the underlying cellular mechanisms remain unclear. The hippocampus undergoes rapid development with inhibitory circuit refinement during the juvenile period. To investigate the effects of neonatal proinflammatory stress on hippocampal development, we examined markers of maturation in the dorsal hippocampus in juvenile rats subjected to neonatal proinflammatory stress. Pups were subjected to subcutaneous injections of lipopolysaccharide on postnatal days (PD) 3 and 5. On PD 18, we assessed density of parvalbumin+ (PV+) interneurons, perineuronal nets (PNNs), astroglial and microglial cells, and morphological complexity by means of fluoimmunohistochemistry. To reveal the state of neuron–microglia communication we performed qPCR on fractalkine and its receptor mRNA. Neonatal proinflammatory stress was found to increase the proportion of animals with PV+ interneurons surrounded by PNNs in the CA1 subfield of the hippocampus in juvenile rats. However, the number of PV+ interneurons per se was not affected. The density and complexity of microglia displayed significant subfield and sex-specific variations in response to neonatal proinflammatory stress, while astrocyte density varied across subfields but was unaffected. Expression of fractalkine (CX3CL1) and its receptor CX3CR1 genes at the mRNA level did not show significant treatment-related changes. Together, these findings suggest that neonatal proinflammatory stress biases the maturation of the juvenile hippocampus towards an increased association between PNN and PV+ interneurons in the CA1 region, and elicits sex-dependent changes in the state of microglia. These alterations may contribute to the impairment of LTP by modifying inhibitory circuits during a sensitive developmental period, as was previously observed.
Claudin-2 levels were analyzed in the hypothalamus of male Sprague–Dawley rats after nephrectomy against the background of developing chronic kidney disease and cardiovascular pathology. PCR results demonstrate a statistically significant increase in claudin-2 mRNA levels in nephrectomized rats compared to sham-operated animals and a significant decrease in its levels after the administration of antibodies to marinobufagenin. Western blot analysis and immunohistochemistry revealed similar changes in claudin-2 protein in the hypothalamus, specifically in neurons of the arcuate nucleus, where a high density of claudin-2-immunopositive cells was observed. The obtained data demonstrate for the first time changes in the brain level of claudin-2 protein, which is well known to be a cation-selective tight junction protein recently identified directly in brain neurons, and also show a relationship between claudin-2 gene expression and the level of marinobufagenin, an endogenous Na/K-ATPase inhibitor.
The rodent somatosensory system, due to its strict somatotopic organization, is a classic and widely used model for studying the influence of sensory experience on brain development and animal behavior. This review is aimed to systematize data on the early behavioral consequences of postnatal vibrissectomy, analyze the limitations of this model, and propose new approaches to overcoming them. The anatomy and ontogeny of the vibrotactile system in laboratory rodents, sensory deprivation and its effects on vibrissal functions, as well as the translational potential of the model are considered. Vibrissa trimming (cutting whiskers), unlike invasive interventions, does not disrupt the structural integrity of the analyzer but selectively restricts the inflow of species-specific sensory information, thereby allowing the investigation of experience-dependent plasticity of the nervous system. The effect of transient vibrissectomy depends on the timing of its application during postnatal ontogeny. Prospects for further development of this model imply (1) a targeted study of deprivation effects on complex forms of learning, decision-making, and the formation of adaptive behavioral strategies; (2) standardization of experimental protocols to minimize stress caused by manipulations and rigid control of social context influences; and (3) the development and implementation of behavioral paradigms for assessing task outcomes, movement kinematics, action sequences, and emerging strategies. The development of various, time-specific, pathogenetically substantiated models of sensory deprivation-based neurological disorders is necessary for the development of corrective therapies aimed at reducing the risks of negative manifestations of childhood neuropsychiatric deficits in adulthood.
The effect of myocardial stretch on calcium kinetics in cardiomyocytes is manifested as a crossover in the superposition of calcium transient (CaT) curves at long and short lengths. CaT curves were recorded using Fura-2 AM in multicellular myocardial strips from the right heart of male Wistar rats in a control group (CONT) and in a group with monocrotaline-induced cardiopulmonary failure (MCT) in an intact state, during the slowing of myosin cross-bridge cycling with 1 µM omecamtiv mecarbil (OM), and during electromechanical uncoupling with 10 µM blebbistatin (BB). It was found that length-dependent, oppositely directed changes in different phases of the CaT decay are less pronounced in the right ventricular (RV) myocardium of the MCT group compared to the CONT group. In the right atrial (RA) myocardium of both groups, the crossover is weakly pronounced. In the ventricular myocardium, OM increases CaT crossover manifestation at different lengths in the early phase of the decay and decreases it in the late phase in the CONT group. In the MCT group, OM decreases CaT crossover manifestation in the RV myocardium in both phases. In the RA myocardium, OM increases CaT crossover manifestation upon myocardial stretch. BB causes the disappearance of CaT crossover in the RV myocardium of both groups. Length-dependent changes of CaT duration are monotonic under BB treatment. Based on the data obtained, we hypothesize that CAT crossover at different lengths in the RV myocardium results from changes in the number of myosin heads in a strongly actin-bound state and the cycling rate of myosin cross-bridges. Furthermore, CaT crossover is modulated by the rate of calcium ion removal from the sarcoplasm. The absence of length-dependent CaT changes in the RA myocardium of rats in both groups is likely due to a more powerful and developed calcium-sequestering system in the RA compared to the RV.
Better development of calculation skills correlates with solving more complex mathematical word problems and applying mathematical skills in real life. The aim of this study was to evaluate event-related potentials (ERPs) in adolescents (n = 60) with different levels of success in solving arithmetic problems using an arithmetic verification task. Participants were presented with a problem (addition, subtraction, or multiplication of two-digit numbers) with 400 ms exposition, followed 700 ms later by an answer (correct or incorrect, exposition 200 ms). There were 1100 ms to calculate from the beginning of the problem presentation until the answer presentation. Upon presentation of a correct answer, participants were required to press a mouse button. Based on the number of correct responses (pressing for correct answers and withholding presses for incorrect answers), subgroups of “more successful” participants (upper quartile of the distribution, n = 15) and “less successful” participants (lower quartile, n = 15) were identified. During perception of a correct answer, the more successful group showed a greater amplitude in the 196–404 ms interval, corresponding to the P300 component, with a maximum over parietal areas. During perception of an incorrect answer, the more successful group demonstrated greater amplitudes in the 112–160 ms interval (P2 component) and the 224–496 ms interval (late positive component). During arithmetic problem solving (first stimulus), the more successful group exhibited a more negative ERP amplitude in parietal and occipital regions within the 528–600 ms and 640–808 ms time intervals. The greater amplitude of the late posterior negativity may indicate more efficient activation of memory resources in this group.
Estrogen plays a significant role in the regulation of cardiac contractility. Estrogen imbalance contributes to the development of atrial fibrillation (AF). The effect of estrogen on the functional remodeling of the atrial myocardium in AF has not been previously studied. We compared the effects of 50 and 100 nM 17β-estradiol (E2) on the contractility of atrial and ventricular cardiomyocytes in rats with paroxysmal AF. We found that in both hearts with normal sinus rhythm and hearts with AF, E2 modulates sarcomere contractility parameters primarily in ventricular cardiomyocytes. In hearts with normal sinus rhythm, E2 had a more pronounced effect on sarcomeric protein phosphorylation in ventricular cardiomyocytes than in atrial cardiomyocytes. In contrast, in AF, incubation with E2 had a greater effect on protein phosphorylation in atrial cardiomyocytes. The effects of E2 on the contractile characteristics of single cardiomyocytes were non-monotonic. These results indicate that estrogen significantly contributes to the remodeling of myocardial contractile function in AF, which is particularly important given the widespread use of hormone replacement therapy.
Reproductive functions are regulated through the hypothalamic–pituitary–gonadal (HPG) axis, whereas metabolism, thermogenesis, and functions of the cardiovascular and nervous systems are controlled via the hypothalamic–pituitary–thyroid (HPT) axis. The primary regulators of these functions are pituitary glycoprotein hormones—gonadotropins in the case of the HPG axis, including luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) in the case of the HPT axis. Acting on structurally related LH and TSH receptors localized in the peripheral components of these axes, LH and TSH stimulate the synthesis of sex steroid and thyroid hormones, respectively. Since the clinical use of gonadotropins can lead to side effects, while TSH is not at all used clinically, the development of alternative pathways for activating LH and TSH receptors is a relevant task. In this context, the low-molecular-weight regulators of these receptors, which interact with their allosteric sites similar in structure and localization, are of particular interest. Furthermore, the activity of the HPG and HPT axes can be controlled by such metabolic hormones as insulin and leptin. This review is devoted to the current state of the problem of developing and applying ligands for the allosteric sites of LH and TSH receptors, as well as the use of insulin and leptin for regulating the HPG and HPT axes in health and pathology. The main focus is on the thieno[2,3-d]-pyrimidine derivatives, developed by the authors, with an LH receptor agonist activity, capable of effectively stimulating testicular and ovarian steroidogenesis and ovulation, as well as allosteric TSH receptor regulators endowed with both inhibitory and stimulatory activity. The authors’ data on the restoration of HPG and HPT axis activity in rats with models of obesity and diabetes mellitus using intranasal insulin and a leptin fragment are discussed in detail.
Migraine is a common neurological disorder whose symptoms are associated with the dysregulation of the dopaminergic system. To evaluate the influence of the dopaminergic system on neuroinflammation in nitroglycerin-induced chronic migraine, we used wild-type rats (DAT-WT) and heterozygous dopamine transporter knockout rats (DAT-HET). The development of neuroinflammation was assessed using common astrocyte (GFAP) and microglial (Iba1) markers, as well as a marker of the pro-inflammatory astrocyte phenotype (S100β), in brain regions involved in pain processing and cognitive impairments in migraine. An increase in the number of S100β-expressing astrocytes was observed in the hippocampal CA1 and CA3 regions in both rat groups with chronic migraine. Differences in activation were found only in the dentate gyrus: DAT-HET rats showed an increased density of GFAP+ and S100β+ cells in the molecular layer, whereas in DAT-WT rats, astrocytes exhibited a shift toward a pro-inflammatory phenotype without changes in their total number. In the ventral thalamic nuclei, microglia density increased during migraine only in DAT-WT animals, with other markers showing no changes. Thus, our results demonstrate a dopamine-dependent pro-inflammatory activation of hippocampal and thalamic glial cells in chronic migraine in rats.
To reduce sex-related differences in the effectiveness of treatment of cardiovascular diseases, it is necessary to identify and compare the features of regulatory processes in the vascular system of male and female organisms. Changes in NO-mediated vasodilation are considered one of the possible mechanisms underlying sex differences. Evidence has recently emerged that the vasodilatory properties of NO, along with other factors, may be mediated by hydrogen sulfide (H2S). The aim of this study was to identify sex-specific features of NO-mediated dilation of cerebral vessels in rats and the contribution of H2S to its implementation. Using the method of intravital microscopy on pial arteries of male and female Sprague–Dawley rats, dilator responses were compared by their number and degree. NO-mediated endothelium-dependent (L-arginine, 10–4 M, 15 min) and endothelium-independent (sodium nitroprusside, 10–5 M, 10 min) dilations were studied, as well as their changes against the background of blockade of endogenous H2S synthesis with propargylglycine, 5 × 10–3 M (10 min). Compared to males, female rats showed a 3.2-fold increase in median dilation values in response to L-arginine at the level of small arteries (caliber < 20 µm) and a 1.6-fold decrease in the dilation degree of large arteries (> 40 µm). Changes in NO-mediated endothelium-independent dilation (a 1.5–2-fold increase in the degree of response to sodium nitroprusside) were shown in arteries with a caliber > 20 µm. These changes may be underlain by the sex differences we found in the contribution of endogenous H2S to dilation: the absence in females of H2S contribution to endothelium-mediated dilator responses of large pial arteries and a 1.3–2.3-fold increase in the contribution of H2S to the degree of endothelium-independent dilation of arteries with a caliber > 20 µm.
The article presents new findings on the evaluation of the effectiveness of physical training on a cycle ergometer in terms of physical performance indicators and force-velocity capabilities of the lower-limb muscles under conditions of sequential exposure to 3-day antiorthostatic hypokinesia (head-down bed rest at –6°, HDBR) and 7-day orthostatic hypokinesia (head-up bed rest at +9.6°, HUBR) as a model of the physiological effects of sequential exposure to weightlessness (microgravity) and lunar gravity during a manned flight to the Moon and stay on its surface. The study involved 10 practically healthy male volunteers (M ± SD: 25.7 ± 4.1 years, 76.1 ± 7.7 kg, 178.8 ± 6.0 cm), who were divided into two equal groups, Control and Training. In the Control group, no preventive measures were applied during bed rest, whereas subjects in the Training group performed daily cycle ergometer training in the orthostatic position, starting from day 4 of bed rest (after transferring from HDBR to HUBR). Force-velocity testing was carried out in the isokinetic mode of a Biodex System 4 Pro dynamometer at angular velocities of 300, 240, 180, 120, and 60 deg/s, a day before bed rest and a day after its completion. The functional state of the cardiorespiratory system and physical performance were evaluated during cardiopulmonary exercise testing (CPET) using an Ergoselect 200 cycle ergometer, two days before the onset and a day after the end of the experimental exposure. A three-stage training protocol (125, 150, 175 W; 5 min per stage) was used. The results of force-velocity testing revealed a decrease in maximum voluntary force, although it was pronounced significantly greater in the Control group than in the Training one. According to the CPET results, the use of cycle ergometer training during HUBR in the Training group led to smaller changes in the dynamics of human cardiorespiratory parameters and, hence, to a smaller decline in performance after the experimental exposure compared to the Control group. Thus, the inclusion of daily cycle ergometer training in the protocol of an experiment with sequential exposure to 3-day HDBR and 7-day HUBR at the hypogravity exposure (HUBR) stage contributed to a lesser development of detraining in the cardiovascular and musculoskeletal systems.
Membrane receptors of the T1R (1–3) “taste” family not only mediate sweet and amino acid taste perception in vertebrates but also participate in the regulation of carbohydrate and lipid metabolism. These receptors, expressed outside the oral cavity, influence the secretion of metabolic hormones, intestinal sugar absorption, and tissue growth/survival; however, many of their effects remain poorly understood. Specifically, the influence of the T1R3 receptor on liver function and overall energy metabolism has been insufficiently characterized and therefore became the objective of the present work. The study was carried out on male mice of the two inbred mouse strains: control C57BL/6J strain carrying the dominant allele of the Tas1r3 gene, encoding the T1R3 receptor with high affinity for sweet substances, and C57BL/6J-Tas1r3 tm1Rfm, a knockout strain lacking the functional Tas1r3 gene. Using indirect calorimetry, it was shown for the first time that the Tas1r3 genotype influences overall energy metabolism. In the postprandial state, the presence of functionally active T1R3 protein promoted total energy expenditure, enhanced carbohydrate oxidation, reduced lipid oxidation, and increased locomotor activity. During fasting, T1R3 contributed to maintaining a higher level of total energy expenditure, stimulated lipid oxidation and locomotor activity. A stimulating effect of T1R3 on hepatic lipogenic activity was revealed, as its presence increased the levels of low- and high-density lipoproteins and total cholesterol. The protein influenced the expression of genes involved in lipid and glycogen metabolism in the liver. In the postprandial state, T1R3 promoted increased expression of the insulin receptor and hepatic lipase. During fasting, T1R3 stimulated the expression of glycogen phosphorylase and hepatic lipase, while suppressing the expression of glycogen synthase. Upon post-fasting glucose entry into the bloodstream, the protein facilitated its utilization for energy needs, limiting the replenishment of glycogen stores. At the same time, its own expression was suppressed. The obtained data provide new insights into the mechanisms underlying T1R3 influence on the regulation of energy metabolism.
The review addresses the possible role of cAMP-dependent signaling in the vertebrate phototransduction cascade and its evolutionary relationship with the canonical cGMP-dependent mechanism. The primary receptor response of vertebrate rods and cones is determined by the opsin → transducin → PDE6 → cGMP → CNG channel pathway, where cAMP is not involved in generating the fast response but may influence sensitivity, adaptation, and the kinetics of photoreceptor recovery. Data on the presence in photoreceptors of cAMP, protein kinase A (PKA), PKA anchoring proteins, cAMP-specific phosphodiesterases, and PKA-dependent protein targets, including Grk7a regulation in Danio rerio cones, are summarized. Two interpretations of cAMP involvement are considered: late integration into an already preformed cGMP-dependent cascade, and the retention of a more ancient signaling module. Evolutionary analysis includes the comparison of opsin- and nonopsin-based photosensitive systems in Hydra magnipapillata, Amphimedon queenslandica, Euglena gracilis, Acropora palmata, Carybdea rastonii, and Tripedalia cystophora. These examples show that cAMP-dependent photosensory solutions are evolutionarily possible but do not form a direct lineage leading to vertebrate cGMP-dependent phototransduction. An intermediate model is proposed, according to which cAMP-dependent modules could have been part of the ancient signaling environment of early sensory cells, whereas in vertebrates they were secondarily embedded into a specialized cGMP-dependent cascade as a regulatory circuit. This interpretation reconciles data on the antiquity of cAMP signaling with the modern subdominant role of cAMP in vertebrate photoreceptors. Particular focus is on distinguishing direct evidence for a phototransduction mechanism from indirect data on the presence of individual signaling cascade components.
Interest in the amyloid precursor protein (APP) initially arose in the study of Alzheimer’s disease, since amyloid β (Aβ), a product of proteolytic processing of APP, was considered key in the pathogenesis of this disease. However, subsequent more detailed and in-depth studies significantly expanded understanding of the functional spectrum of APP family proteins and demonstrated their involvement in many important physiological processes. Currently, APP is considered as a regulatory hub that forms a network of interacting proteins involved in synaptic and neural plasticity, which are a fundamental basis for learning, memory, cognition and behavior. This review analyzes and summarizes insights into the physiological role of the APP and its proteolytic fragments. Problems and the most promising areas for further development are also discussed.
Blood esterases represent a system of functionally interconnected and partially interchangeable enzymes that play an important role in maintaining homeostasis and implementing the signaling, trophic, and protective functions. These esterases collectively forms the body’s esterase profile—a complex dynamic indicator reflecting the functional capacity of the internal environment to hydrolyze and neutralize a wide spectrum of substances containing ester bonds. The review summarizes current data on the diagnostic and prognostic capabilities of the master enzymes of the esterase profile: acetylcholinesterase, butyrylcholinesterase, carboxylesterase, paraoxonase 1, esterase D, carbonic anhydrase, neurotoxic (neuropathy target) esterase, and serum albumin. Changes in the activity or concentration of these proteins are associated with a wide range of pathological conditions: organophosphate poisoning, cardiovascular diseases, diabetes mellitus, metabolic disorders, inflammatory processes, infections (including COVID-19), oncological and neurodegenerative diseases. It is emphasized that isolated assessment of the level and/or activity of individual enzymes has limited potential for clinical diagnosis. The presented data indicate the promise of integrative esterase profile analysis as a multimarker tool capable of improving the accuracy of diagnosis, risk stratification, and prognosis of various pathological conditions.
Obesity and pathogenetically related cardiovascular diseases (CVDs) are among the most significant public health challenges worldwide. By exerting a combined negative impact on health, they substantially increase disability and mortality rates of the global population. Bariatric surgery is currently the most effective treatment for obesity, and the results of numerous clinical trials demonstrate its positive effects on the course of such CVDs as arterial hypertension, coronary artery disease, atrial fibrillation, and chronic heart failure. However, data on the physiological and molecular biological basics of these effects remain relatively scarce. The mechanisms underlying the beneficial influence of bariatric interventions on CVDs can be divided into those dependent on and those independent of body weight loss. Experimental studies in animals, conducted under controlled laboratory conditions, enable the identification of the major pathways responsible for the compensation of CVDs following gastrointestinal surgical interventions in obesity. In this systematic review, we analyze the available experimental studies investigating the impact of bariatric surgery on the manifestations of cardiovascular pathology using appropriate models, including arterial hypertension, diabetic cardiomyopathy, myocardial ischemia–reperfusion injury, and obesity‑induced myocardial dysfunction. It is shown that nearly all research in this area has been performed in rodents. Bariatric procedures, particularly gastric bypass and sleeve gastrectomy, are accompanied by the normalization of obesity‑induced left ventricular systolic and diastolic dysfunction, reduction of myocardial fibrosis in diabetic cardiomyopathy, reduction of infarct size following myocardial ischemia–reperfusion injury, and a decrease in the incidence and severity of arterial hypertension. The implicated molecular mechanisms include the activation of AMP‑activated protein kinase, increased production and bioavailability of nitric oxide, and elevated stimulated secretion levels of glucagon‑like peptide‑1. It is evident that the molecular mechanisms of the beneficial cardiovascular effects of bariatric surgery warrant further investigation.
Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat type 2 diabetes mellitus and obesity, promoting glycemic control and body weight reduction. Beyond its metabolic effects, GLP-1 is known to influence renal function and water-electrolyte balance. Currently, long-acting GLP-1 agonists with a half-life of about one week are being increasingly used; however, their natriuretic action remains unexplored. This study was aimed to evaluate the effects of semaglutide-induced prolonged activation of GLP-1 receptors on water-salt metabolism in healthy rats, including changes in renal sensitivity to NaCl loads and diuretics. The study was carried out on sexually mature Wistar rats of both sexes (20 males and 140 females); semaglutide was administered at doses of 0.125–8 nmol per 100 g body weight. It was shown for the first time that semaglutide exerts a pronounced diuretic and natriuretic effect in rats, particularly during the first 2 h post-injection, with increased sodium excretion persisting for at least 8 h. A higher renal sensitivity to semaglutide was revealed in females. Following semaglutide administration, food intake decreased 2.1–2.7-fold over two days, water intake decreased 2.5-fold over the first day, and NaCl solution intake decreased 5–30-fold over three days. The concomitant increase in serum total protein and albumin levels during this period indicates hemoconcentration and, presumably, the development of hypovolemia. At 48 and 72 h following semaglutide administration, the natriuretic response to NaCl loading was reduced, the efficacy of furosemide was increased, and the efficacy of hydrochlorothiazide was decreased. This likely reflects compensatory responses of tubular sodium transport, specifically, increased sodium reabsorption in the thick ascending limb of the loop of Henle. The obtained data indicate the development of sodium deficiency in the body over three days following the administration of a long-acting GLP-1 agonist, which may have clinical implications for the therapy of cardiovascular diseases.
Adenosine is a neuromodulator that plays an important role in the regulation of many physiological processes in the body under normal and pathological conditions. Dysfunction of the brain adenosine system leads to a number of disorders, including convulsive epilepsy, anxiety, depression, chronic pain, cognitive impairments, and social behavior deficits. The role of the adenosine system in the pathogenesis of non-convulsive absence epilepsy and comorbid behavioral and cognitive impairments remains poorly understood. In the present study, using a genetic model of human absence epilepsy (WAG/Rij rats), we investigated the effect of caffeine, a non-selective adenosine A1/A2A receptor antagonist, on absence epilepsy, comorbid depression, anxiety, cognitive functions, pain sensitivity, and social dominance. Chronic 14-day caffeine administration (20 mg/kg, i.p.) reduced the number, amplitude, asymmetry index, and spectral power density of spike-wave discharges, as well as anxiety and depression levels, while increasing locomotor activity. However, it did not affect discharge duration, conditioned fear memory, pain sensitivity, or social dominance in the tube test. These results suggest that moderate doses of caffeine may be useful for alleviating absence epilepsy and comorbid anxiety- and depressive-like behavioral disorders.
A specific light-dependent blocker of calcium-permeable AMPA channels was obtained in a recently developed series of azobenzene-spermines (ABSPs). At micromolar concentrations, ABSPs also acted on NMDA receptors, exhibiting a number of features suggesting that their effects were more complex than simply light-dependent pore blocking. For compound ABSP-5, whose action was weakly light-dependent, it was found that significant transient current changes appeared upon switching the blue light (450 nm wavelength) on and off. The aim of this work was to elucidate the mechanisms of interaction of cis- and trans-forms of ABSP-5 with the NMDA receptor channel. The experiments were carried out using the whole-cell patch-clamp technique on native NMDA receptors of pyramidal neurons in the CA1 region of the rat hippocampus. It was shown that NMDA receptors are effectively inhibited by both cis- and trans-forms of ABSP-5 via an open-channel blockade mechanism, although the kinetics of action and the voltage dependence of the two forms of ABSP-5 differ significantly. Cis-ABSP-5 interacts with a deep site within the channel and exhibits fast kinetics. Trans-ABSP-5 has a slow kinetics and binds close to the membrane surface. This explains why, upon switching the light on and off, a new action equilibrium is established first for the cis-form, followed by the development of the effect of the ABSP-5 trans-form. Thus, we have shown for the first time that the NMDA receptor channel contains a site that can be specifically blocked by cis-azobenzenes, which are active upon exposure to light. This result opens up the possibility for further designing of specific light-controlled compounds with an inverted light dependence, which will be in demand in experimental research.
