Changes In Locomotor Activity Research Articles

Effects of Dendropanax morbiferus Leaf Extract on Sleep Parameters in Invertebrate and Vertebrate Models.

Dendropanax morbiferus is highly valued in traditional medicine and has been used to alleviate the symptoms of numerous diseases owing to its excellent antioxidant activity. This study aimed to evaluate the sleep promotion and related signaling pathways of D. morbiferus extract (DE) via behavioral analysis, molecular biological techniques, and electrophysiological measurements in invertebrate and vertebrate models. In Drosophila, the group treated with 4% DE experienced decreased subjective nighttime movement and sleep bout and increased total sleeping time. Moreover, substantial changes in locomotor activity, including distance moved, velocity, and movement, were confirmed in the 4% DE-treated group. Compared to Drosophila in which insomnia and oxidative stress were induced by exposure to 0.1% caffeine, the DE-treated group improved sleep-related parameters to the level of the normal group. In the Drosophila model, exposure to 4% DE upregulated the expression of gamma-aminobutyric acid (GABA)-related receptors and serotonin receptor (5-HT1A), along with the expression of antioxidant-related factors, glutathione, and catalase. In the pentobarbital-induced sleep test using ICR mice, the duration of sleep was markedly increased by high concentration of DE. In addition, through the electroencephalography analysis of SD-rats, a significant increase in non-rapid-eye-movement sleep and delta waves was confirmed with high concentrations of DE administration. The increase in sleep time and improvement in sleep quality were confirmed to be related to the expression of altered GABA receptors and the enhancement of the contents of the neurotransmitters GABA and serotonin (5-HT) because of high DE administration. High-dose administration of DE also increased the expression of antioxidant-related factors in the brain and significantly decreased malondialdehyde content. Taken together, DE induced improvements in sleep quantity and quality by regulating neurotransmitter content and related receptor expression, along with high antioxidant activity, and may have a therapeutic effect on sleep disorders.

Valerenic acid reduces anxiety-like behavior in young adult, female (C57BL/6J) mice

Extracts from the plant Valeriana officinalis are marketed as an herbal remedy to treat anxiety and insomnia. Valerenic acid (VA) is a major chemical component of Valeriana extracts. To date, there is relatively little information about how VA affects behavior. The purpose of these experiments was to (1) test whether administration of VA induces measurable changes in anxiety-like, depression-like, or locomotor behaviors; (2) determine whether the effects of VA on behavior are dose-dependent; and (3) compare the effects of VA on behavior to those of diazepam, a commonly prescribed treatment for anxiety. Young adult, female mice (C57BL/6J; 3–4 months old; 12 mice/group) were given one of three dosages of VA (3 mg/kg, 6 mg/kg, or 12 mg/kg), diazepam (1 mg/kg), or a vehicle control solution (20% ethanol v/v) by intraperitoneal injection. Thirty minutes after injection, each mouse was tested in the elevated plus maze (EPM), open field test (OFT), and tail suspension test (TST), in that order. All tests were video recorded and analyzed for relevant behavioral parameters. The results demonstrated that VA treatment effectively reduced multiple anxiety-related behaviors measured in the EPM. In fact, at a dose of 12 mg/kg, the anxiolytic effect of VA was just as robust as that of diazepam. Furthermore, the effects of VA on behavior were specifically anxiolytic, as VA did not induce changes in locomotor activity in the OFT, or depression-related behavior as measured in the TST. Our results provide strong support for VA as a putative anxiolytic drug.

Influence of the dose of ketamine used on schizophrenia-like symptoms in mice: A correlation study with TH, GAD67, and PPAR-γ

Schizophrenia is a chronic, debilitating mental illness that has not yet been completely understood. In this study, we aimed to investigate the effects of different doses of ketamine, a non-competitive NMDA receptor antagonist, on the positive- and negative-like symptoms of schizophrenia. We also explored whether these effects are related to changes in the immunoreactivity of GAD67, TH, and PPAR-γ in brain structures. To conduct the study, male mice received ketamine (20–40 mg/kg) or its vehicle (0.9 % NaCl) intraperitoneally for 14 consecutive days. We quantified stereotyped behavior, the time of immobility in the forced swimming test (FST), and locomotor activity after 7 or 14 days. In addition, we performed ex vivo analysis of the immunoreactivity of GAD, TH, and PPAR-γ, in brain tissues after 14 days. The results showed that ketamine administration for 14 days increased the grooming time in the nose region at all tested doses. It also increased immobility in the FST at 30 mg/kg doses and decreased the number of rearing cycles during stereotyped behavior at 40 mg/kg. These behavioral effects were not associated with changes in locomotor activity. We did not observe any significant alterations regarding the immunoreactivity of brain proteins. However, we found that GAD and TH were positively correlated with the number of rearing during the stereotyped behavior at doses of 20 and 30 mg/kg ketamine, respectively. GAD was positively correlated with the number of rearing in the open field test at a dose of 20 mg/kg. TH was inversely correlated with immobility time in the FST at a dose of 30 mg/kg. PPAR-γ was inversely correlated with the number of bouts of stereotyped behavior at a dose of 40 mg/kg of ketamine. In conclusion, the behavioral alterations induced by ketamine in positive-like symptoms were reproduced with all doses tested and appear to depend on the modulatory effects of TH, GAD, and PPAR-γ. Conversely, negative-like symptoms were associated with a specific dose of ketamine.

SAT649 Org43553, The First Low-molecular-weight Agonist Of The Human Luteinizing Hormone Receptor Induces Leanness And Energy Expenditure In Mice

Abstract Disclosure: D. Lizneva: None. A. Gumerova: None. K. Ievleva: None. O. Barak: None. F. Korkmaz: None. J. Gimenez Roig: None. T. Frolinger: None. G. Pevnev: None. F. Sultana: None. N. Kramskiy: None. S. Wizman: None. M. Orloff: None. A.R. Pallapati: None. S. Rojekar: None. V. Ryu: None. O. Moldavski: None. T. Yuen: None. M. Zaidi: None. We provide compelling evidence that LH is a pro–lean hormone, and that ORG43553, the first low-molecular-weight agonist of the luteinizing hormone receptor (LHCGR) induces leanness and promotes energy expenditure in mice. We detected Lhcgr transcripts in white adipose tissue (WAT) depots in male and female C57BL/6 mice (qPCR, IHC, RNAscope, Sanger sequencing), but not in Lhcgr-/- mice. Intraperitoneal AlexaFluor-488–labeled hCG bound to gonadal and subcutaneous fat pads in wild type mice, but not in Lhcgr-/- mice. Following i.v. 89Zr–LH injection, radioactivity was detected in mesenteric, inguinal and gonadal WAT. LH, hCG and ORG43553 rapidly induced ERK1/2 phosphorylation in differentiated 3T3.L1 cells. Female and male Lhcgr+/- mice on normal chow and high–fat diet, respectively, became obese, importantly, without changes in sex steroids. The gene–dosage effect of Lhcgr depletion suggests a dominant physiologic action of LH on body composition. 14–week–old male C57BL/6 mice were fed on high–fat diet and injected, i.p., with LH, hCG or vehicle, twice–a–week, for 6 weeks. Both LH and hCG markedly reduced body fat accrual (qNMR) but triggered a rise in serum testosterone. The hCG–induced lean phenotype persisted despite androgen receptor blockade by flutamide—confirming that the pro–lean actions of LH and hCG were largely independent of testosterone. Furthermore that LH failed to inhibit fat accrual in Lhcgr-/- mice testified to its action via the LHCGR. Injection of ORG43553 into male C57BL/6 mice for 9 weeks caused a significant reduction in fat mass (qNMR), with reduced WAT weight in fat depots. Remarkably, serum testosterone remained unchanged confirming that the anti–adiposity effect of ORG43553 was independent of testosterone. To study the mechanism of LHCGR activation on body fat, 3T3.L1 adipocytes were treated with hCG or ORG43553 for 12 hours. This resulted in reduced oil droplet accumulation. 3T3-L1–derived organoids treated with LH, hCG or ORG43553 also displayed a substantial reduction in the differentiated layer compared to vehicle–treated organoids. To study whether, in addition to reducing adipocyte differentiation, LHCGR agonism also enhanced thermogenesis, 3T3-L1 adipocytes were pretreated with ORG43553 for 1 hour before measuring oxygen consumption rate (OCR) on a Seahorse Xf96 Analyzer. ORG43553 increased OCR at baseline and upon oligomycin exposure, indicating mitochondria proton leak (thermogenesis). To confirm increased energy expenditure in vivo, mice were injected, s.c., with ORG43553 or vehicle. Oxygen consumption (VO2) and energy expenditure (EE) increased acutely in ORG43553–treated mice, with no change in locomotor activity. The findings suggest that ORG45335, which has been tested in humans for infertility, can potentially become a candidate drug for obesity. Presentation: Saturday, June 17, 2023

SAT002 Liver-specific Loss Of The Nuclear Receptor Co-regulator ARGLU1 Protects Against Diet-induced Obesity In Female Mice Independent Of Food Intake And Energy Expenditure

Abstract Disclosure: S.B. Cash: None. L. Magomedova: None. R. Tsai: None. C.L. Cummins: None. Arginine and glutamate rich 1 (ARGLU1) has been shown to be a co-regulator for several nuclear receptors including ER, GR and the peroxisome proliferator-activated receptors (PPARs), which are key modulators of nutrient metabolism. We have previously reported that loss of ARGLU1 in the liver protects aged male mice against high-fat diet induced obesity and type 2 diabetes [1]. Here, we assessed the importance of ARGLU1 in lipid and carbohydrate metabolism in aged female mice and used indirect calorimetry to understand the metabolic basis of the resistance to weight gain observed with liver-specific loss of ARGLU1. Aged (11-month-old) female wildtype floxed-Arglu1 mice (Arglu1fl/fl) and liver-specific Arglu1-null mice (Arglu1LKO) were fed a high fat, high cholesterol diet (HFD, 42% calories from fat, TD.88137 Envigo) for 12-weeks (N=7-17). Female mice were housed in Promethion Metabolic Cages (Sable Systems) at room temperature for 5 days during which their food intake, water intake, physical activity, O2 consumption, and CO2 production were measured (N=5-7). Female mice were also subjected to a glucose tolerance test and insulin tolerance test (N=4-8). In agreement with our previous results in male Arglu1LKO mice [1], female Arglu1LKO mice were resistant to diet-induced obesity with final body weights compared to HFD-fed Arglu1fl/fl mice of 30.6 ± 0.9 g vs 35 ± 1 g (P<0.05). Likewise, female Arglu1LKO mice were more glucose tolerant and insulin tolerant compared to HFD-fed Arglu1fl/fl mice. The metabolic cage data showed no change in food intake, locomotor activity or energy expenditure between HFD-fed Arglu1fl/fl and Arglu1LKO mice when accounting for body mass as a covariate (ANCOVA, CalR). Surprisingly, HFD-fed female Arglu1LKO mice had significantly higher water intake compared to HFD-fed Arglu1fl/fl mice (P<0.02). These data support the conclusion that resistance to diet-induced obesity in Arglu1LKO mice is independent of sex. To our surprise, based on the metabolic cage data, we conclude that the mechanism by which Arglu1LKO mice are resistant to diet induced obesity is not due to enhanced energy expenditure or decreased food intake. Future studies will explore whether differential intestinal lipid absorption (independent of food intake) could account for the differences we observed in weight gain between the genotypes. [1] Magomedova, L., Tsai, R., & Cummins, C. L. (2017, April). Hepatic Ablation of the Nuclear Receptor Coactivator, ARGLU1, Is Protective Against the Development of Type 2 Diabetes and Fatty Liver in High-Fat Diet Fed Mice. In 99th Annual Meeting of the Endocrine Society. Endocrine Society. Presentation: Saturday, June 17, 2023

Methods for Exploring the Circuit Basis of Ethanol-Induced Changes in Drosophila Group Locomotor Activity.

Locomotion is a behavioral readout that can be used to understand responses to specific stimuli or perturbations. The fly Group Activity Monitor (flyGrAM) provides a high-throughput and high-content readout of the acute stimulatory and sedative effects of ethanol. The flyGrAM system is adaptable and seamlessly introduces thermogenetic or optogenetic stimulation to dissect neural circuits underlying behavior and tests responses to other volatilized stimuli (humidified air, odorants, anesthetics, vaporized drugs of abuse, etc.). The automated quantification and readout of activity provide users with a real-time representation of the group activity within each chamber throughout the experiment, helping users to quickly determine proper ethanol doses and duration, run behavioral screens, and plan follow-up experiments.

RIT1 deficiency alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

MOVEMENT ACTIVITY OF ROUND GOBY (NEOGOBIUS MELANOSTOMUS PALLAS, 1814) UNDER THE INFLUENCE OF GEOMAGNETIC FIELDS

Introduction. Behavioral traits of fish are an important manifestation of their response to external stimuli. Locomotor activity reflects the influence of specific factors on fish behavior and the role they play in their lives. Among the least studied factors are fluctuations in the geomagnetic field and their impact on the locomotor activity of the round goby Neogobius melanostomus Pallas, 1814. Aim. The aim of this study was to investigate the influence of fluctuations in the geomagnetic field on the locomotor activity of the commercially important speciesof benthic ichthyofauna, the round goby Neogobius melanostomus Pallas, 1814, in the Black Sea. Methods. The ichthyological material was collected in the coastal waters of the Odesa Bay, ranging from Cape Northern Odesa to Cape Velikyi Fontan, during a scientific research survey conducted by the I.I. Mechnikov Odesa National University (ONU). Laboratory investigations were conducted in the aquarium room of the Aquatic Biology and General Ecology Department of the I.I. Mechnikov Odesa National University. Hourly changes in fish locomotor activity were recorded and analyzed as a result of the study. During the specified observation period, periods of increased geomagnetic activity were identified and compared to periods when this activity was within normal range. An original methodology called “Computer Vision Method” was employed for processing the visual data and tracking of the laboratory animals. Results. The maximum values of geomagnetic activity during the observation period, classified as a first intensity magnetic storm of class G1, were observed on February 3, 2022, from 6 to 12 hours, and on February 4 and 10, 2022, from 15 to 21 hours. When comparing the levels of fish locomotor activity during these time intervals with their activity during the time intervals on days with minimal geomagnetic activity (February 8, 9, and 15, 2022), a decrease in locomotor activity of individuals during magnetic storms of 27% to 42% can be observed. Conclusion. The fluctuations in locomotor activity of the round goby during increased geomagnetic activity up to the level of magnetic storms indicate the ability of this species to perceive magnetic fields and respond to changes in its properties. Specifically, when the Kp-index values corresponded to a first intensity geomagnetic storm (G1), a decrease in fish locomotor activity was observed compared to the activity during the same time intervals on days with minimal geomagnetic activity.

Arsenic Impairs Differentiation of Human Induced Pluripotent Stem Cells into Cholinergic Motor Neurons.

Arsenic exposure during embryogenesis can lead to improper neurodevelopment and changes in locomotor activity. Additionally, in vitro studies have shown that arsenic inhibits the differentiation of sensory neurons and skeletal muscle. In the current study, human-induced pluripotent stem (iPS) cells were differentiated into motor neurons over 28 days, while being exposed to up to 0.5 μM arsenic. On day 6, neuroepithelial progenitor cells (NEPs) exposed to arsenic had reduced transcript levels of the neural progenitor/stem cell marker nestin (NES) and neuroepithelial progenitor marker SOX1, while levels of these transcripts were increased in motor neuron progenitors (MNPs) at day 12. In day 18 early motor neurons (MNs), choline acetyltransferase (CHAT) expression was reduced two-fold in cells exposed to 0.5 μM arsenic. RNA sequencing demonstrated that the cholinergic synapse pathway was impaired following exposure to 0.5 μM arsenic, and that transcript levels of genes involved in acetylcholine synthesis (CHAT), transport (solute carriers, SLC18A3 and SLC5A7) and degradation (acetylcholinesterase, ACHE) were all downregulated in day 18 early MNs. In day 28 mature motor neurons, arsenic significantly downregulated protein expression of microtubule-associated protein 2 (MAP2) and ChAT by 2.8- and 2.1-fold, respectively, concomitantly with a reduction in neurite length. These results show that exposure to environmentally relevant arsenic concentrations dysregulates the differentiation of human iPS cells into motor neurons and impairs the cholinergic synapse pathway, suggesting that exposure impairs cholinergic function in motor neurons.

Becoming adults: exploring the late ontogeny of the human talus

IntroductionThe talus plays an important role in receiving and dissipating the forces and linking the leg and the foot. As such, it is of paramount importance to analyze how its morphology, internal and external, changes during late ontogeny and through adolescence.MethodTo explore both the external shape and the internal architecture of the talus, Geometric Morphometrics and trabecular analysis have been applied to a sample of 35 tali from modern human juveniles aged between 5 and 15 years old (Middle Neolithic (4800–4500 BCE) to mid-20th century).ResultsResults show that, as the overall size of the talus increases, the shape and orientation of talar facets also change. The youngest individuals exhibit a functional talus that is still characterized by a relatively immature shape (e.g., subtly expressed margins of articular surfaces) with articular facets only minimally rotated towards an adult configuration. In adolescents, talar shape has achieved adult form after the age of 11, with all the articular facets and posterior processes well-developed. Considering internal morphology, trabecular bone varies between age classes. While Bone Volume Fraction shifts during the age 5–15 range, Degree of Anisotropy is relatively more stable over the developmental period examined in the study since it exhibits smaller variations between age classes.DiscussionThis study examined the late ontogeny of the human talus by considering both internal and external morphology. Results suggest that, although the locomotion has already assumed an adult-like pattern, the exploration of late talar growth may help understand how the talus adapts to changes in locomotor activity and how it responds to the increase in weight. Present results can be used to a better understanding of talar plasticity, improving interpretations of adult human talar form.

Chronic social stress blunts core body temperature and molecular rhythms of Rbm3 and Cirbp in mouse lateral habenula

Chronic social stress in mice causes behavioural and physiological changes that result in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity in mice that are resilient or susceptible to stress, we measured core body temperature (Tcore) before and after exposure to chronic social defeat stress (CSDS). We found that Tcore amplitudes of stress-resilient and susceptible mice are dampened during exposure to CSDS. However, following CSDS, resilient mice recovered temperature amplitude faster than susceptible mice. Furthermore, the interdaily stability (IS) of temperature rhythms was fragmented in stress-exposed mice during CSDS, which recovered to control levels following stress. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression of Prok2 - an output signal of the suprachiasmatic nucleus. We also determined that expression of thermosensitive genes Rbm3 and Cirbp in the lateral habenula (LHb) were blunted 1 day after CSDS. Rhythmic expression of these genes recovered 10 days later. Overall, we show that CSDS blunts Tcore and thermosensitive gene rhythms. Tcore rhythm recovery is faster in stress-resilient mice, but Rbm3 and Cirbp recovery is uniform across the phenotypes.

USP18 overexpression protects against spinal cord ischemia/reperfusion injury via regulating autophagy

BackgroundSpinal cord ischemia–reperfusion injury (SCII) is usually caused by spinal surgery, often leading to severe neurological deficits. The ubiquitin-specific protease 18 (USP18) plays a significant role in neurological diseases. ObjectiveThe present study was designed to assess the effects and mechanisms of USP18 on SCII. MethodsBy inducing transient aortic occlusion and subsequent reperfusion, a rat model of SCII was successfully established. The Basso-Beattie-Bresnahan scores, the inclined plane test, and hematoxylin and eosin (HE) were used to measure locomotor activity and histological changes in the injured spinal cords. Moreover, the SCII cell model was established using PC12 cells under oxygen-glucose deprivation and reoxygenation (OGD/R). Proinflammatory factors (TNF-α, IL-6, and INF-α) were examined using an ELISA kit. Cell apoptosis was assessed by Annexin V-FITC/PI double-staining and TUNEL assays. Western blot was used to detect the expression levels of proteins related to apoptosis and autophagy. ResultsUSP18 expression was decreasedin vivo and in vitro SCII models. The upregulation of USP18 ameliorated hind limbs' motor function, inhibiting inflammation and apoptosis after SCII in rats. USP18 overexpression in vitro may protect PC12 cells from OGD/R-induced damage by modulating inflammatory responses and apoptosis. Moreover, Overexpression of USP18 enhanced autophagy to inhibit cell apoptosis induced by SCII in vivo and in vitro. ConclusionsIn summary, USP18 overexpression protects against SCII via regulating autophagy.

Changes of Locomotor Activity by Dopamine D2, D3 Agonist Quinpirole in Mice Using Home-cage Monitoring System.

: As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system. : The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA. : After the quinpirole administration, the 24-hour total locomotor activity did not change (p = 0.169), but activities were significantly increased in the 12-hour dark phase sum (p = 0.013) and decreased in the 12-hour light phase sum (p = 0.009). Significant increases in the activities were observed in the dark-light difference (p = 0.005) and dark-light ratio (p = 0.005) as well. : This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms.

Loss of Astrocytic µ Opioid Receptors Exacerbates Aversion Associated with Morphine Withdrawal in Mice: Role of Mitochondrial Respiration.

Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of the Oprm1 gene encoding µ opioid receptor 1 was selectively deleted from brain astrocytes in Oprm1 inducible conditional knockout (icKO) mice. These mice did not exhibit changes in locomotor activity, anxiety, or novel object recognition, or in their responses to the acute analgesic effects of morphine. Oprm1 icKO mice displayed increased locomotor activity in response to acute morphine administration but unaltered locomotor sensitization. Oprm1 icKO mice showed normal morphine-induced conditioned place preference but exhibited stronger conditioned place aversion associated with naloxone-precipitated morphine withdrawal. Notably, elevated conditioned place aversion lasted up to 6 weeks in Oprm1 icKO mice. Astrocytes isolated from the brains of Oprm1 icKO mice had unchanged levels of glycolysis but had elevated oxidative phosphorylation. The basal augmentation of oxidative phosphorylation in Oprm1 icKO mice was further exacerbated by naloxone-precipitated withdrawal from morphine and, similar to that for conditioned place aversion, was still present 6 weeks later. Our findings suggest that µ opioid receptors in astrocytes are linked to oxidative phosphorylation and they contribute to long-term changes associated with opioid withdrawal.

Сhanges of trace elements in the cerebellum and their influence on the rats behavior in elevated plus maze in the acute period of mild blast-induced brain injury

BackgroundIn connection with the widespread use of explosive devices in military conflicts, in particular in Ukraine, is relevant to detect the biometals changes in the cerebellum and determine the presence of their influence on the behavior changes of rats in the elevated plus maze in the acute period of a mild blast-traumatic brain injury (bTBI). MethodsThe selected rats were randomly divided into 3 groups: Group I - Experimental with bTBI (with an excess pressure of 26–36 kPa), Group II - Sham and Group III - Intact. Behavior studies was in the elevated plus maze. Brain spectral analysis was with using of energy dispersive X-ray fluorescence analysis, after obtaining the quantitative mass fractions of biometals, the ratios of Cu/Fe, Cu/Zn, Zn/Fe were calculated and the data between the three groups were compared. ResultsThe results showed an increase in mobility in the experimental rats, which indicates functional disorders of the cerebellum in the form of maladaptation in space. Changes in cognitive activity also is an evidence of cerebellum suppression, which is indicated by changes in vertical locomotor activity. Grooming time was shortened. We established a significant increase in Cu/Fe and Zn/Fe ratios in the cerebellum, a decrease in Cu/Zn. ConclusionsChanges in the Cu/Fe, Cu/Zn, and Zn/Fe ratios in the cerebellum correlate with impaired locomotor and cognitive activity in rats in the acute posttraumatic period. Accumulation of Fe on the 1st and 3rd day leads to disturbance of the Cu and Zn balance on the 7th day and starts a "vicious cycle" of neuronal damage. Cu/Fe, Cu/Zn, and Zn/Fe imbalances are secondary factors in the pathogenesis of brain damage as a result of primary bTBI.

Development of Novel Substituted 1,2,3,4-tetrahydro Cyclohex-1,2,3-trihydro Cyclopenta [B] Indole Derivatives as Potential Therapeutic Agents

Abstract: The current study aims to synthesize, characterize, and evaluate a specific class of heterocyclic compounds called fused polycyclic indoles, in combination with carbazoles, carbolines, and their partially saturated counterparts. These compounds have been known to have potent biological activity. The study's procedures involve synthesizing these compounds and evaluating them for central nervous system activity. Results showed that all the compounds had CNS-depressing effects in mice. Some compounds, such as YA1 and YA5, were found to have a stronger CNS-depressing activity than others. All compounds tested, YA1 to YA7, caused more than 50% change in locomotor activity when compared to a standard drug. YA3 and YA5 were found to have the highest activity at 86.2% and 83.9% respectively after 120 minutes of administration at a dose of 100 mg/kg. In addition, the acute oral toxicity studies showed that YA3 was non-toxic and YA5 was found to be toxic. The findings of the study provide evidence that these title compounds have good CNS activity.

The alleviative effect of Calendula officinalis L. extract against Parkinson's disease-like pathology in zebrafish via the involvement of autophagy activation.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, effective preventative or therapeutic agents for PD remain largely limited. Marigold Calendula officinalis L. (CoL) has been reported to possess a wide range of biological activities, but its neuroprotective activity including anti-neurodegenerative diseases is unclear. Here, we aim to investigate whether the extract of CoL (ECoL) has therapeutic activity on PD. We identified the chemical composition of flavonoid, an important active ingredient in ECoL, by a targeted HPLC-Q-TOF-MS analysis. Subsequently, we evaluated the anti-PD effect of ECoL by using zebrafish PD model induced by 1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine (MPTP). After ECoL+MPTP co-treatments, the changes of dopaminergic neurons, neural vasculature, nervous system, and locomotor activity were examined, respectively. The expressions of genes related to neurodevelopment and autophagy were detected by RT-qPCR. Further, the interaction between autophagy regulators and ECoL flavonoids was predicted using molecular docking method. As a result, 5 kinds of flavonoid were identified in ECoL, consisting of 121 flavones and flavonols, 32 flavanones, 22 isoflavonoids, 11 chalcones and dihydrochalcones, and 17 anthocyanins. ECoL significantly ameliorated the loss of dopaminergic neurons and neural vasculature, restored the injury of nervous system, and remarkably reversed the abnormal expressions of neurodevelopment-related genes. Besides, ECoL notably inhibited the locomotor impairment in MPTP-induced PD-like zebrafish. The underlying anti-PD effect of ECoL may be implicated in activating autophagy, as ECoL significantly upregulated the expressions of genes related to autophagy, which contributes to the degradation of α-synuclein aggregation and dysfunctional mitochondria. Molecular docking simulation showed the stable interaction between autophagy regulators (Pink, Ulk2, Atg7, and Lc3b) and 10 main compounds of flavonoid in ECoL, further affirming the involvement of autophagy activation by ECoL in anti-PD action. Our results suggested that ECoL has the anti-PD effect, and ECoL might be a promising therapeutic candidate for PD treatment.

Evaluation of Some Safety Parameters of Dual Histamine H3 and Sigma-2 Receptor Ligands with Anti-Obesity Potential.

Many studies have shown the high efficacy of histamine H3 receptor ligands in preventing weight gain. In addition to evaluating the efficacy of future drug candidates, it is very important to assess their safety profile, which is established through numerous tests and preclinical studies. The purpose of the present study was to evaluate the safety of histamine H3/sigma-2 receptor ligands by assessing their effects on locomotor activity and motor coordination, as well as on the cardiac function, blood pressure, and plasma activity of certain cellular enzymes. The ligands tested at a dose of 10 mg/kg b.w. did not cause changes in locomotor activity (except for KSK-74) and did not affect motor coordination. Significant reductions in blood pressure were observed after the administration of compounds KSK-63, KSK-73, and KSK-74, which seems logically related to the increased effect of histamine. Although the results of in vitro studies suggest that the tested ligands can block the human ether-a-go-go-related gene (hERG) potassium channels, they did not affect cardiac parameters in vivo. It should be noted that repeated administration of the tested compounds prevented an increase in the activity of alanine aminotransferase (AlaT) and gamma-glutamyl transpeptidases (gGT) observed in the control animals fed a palatable diet. The obtained results show that the ligands selected for this research are not only effective in preventing weight gain but also demonstrate safety in relation to the evaluated parameters, allowing the compounds to proceed to the next stages of research.

The Antinociceptive Activity of (E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide in Mice Is Reduced by (E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide Through Opposing Modulatory Mechanisms at the α7 Nicotinic Acetylcholine Receptor.

The primary objective of this study was to characterize the pharmacological and behavioral activity of 2 novel compounds, DM497 [(E)-3-(thiophen-2-yl)- N -(p-tolyl)acrylamide] and DM490 [(E)-3-(furan-2-yl)- N -methyl- N -(p-tolyl)acrylamide], structural derivatives of PAM-2, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). A mouse model of oxaliplatin-induced neuropathic pain (2.4 mg/kg, 10 injections) was used to test the pain-relieving properties of DM497 and DM490. To assess possible mechanisms of action, the activity of these compounds was determined at heterologously expressed α7 and α9α10 nAChRs, and voltage-gated N-type calcium channel (Ca V 2.2) using electrophysiological techniques. Cold plate tests indicated that 10 mg/kg DM497 was able to decrease neuropathic pain in mice induced by the chemotherapeutic agent oxaliplatin. In contrast, DM490 induced neither pro- nor antinociceptive activity but inhibited DM497's effect at equivalent dose (30 mg/kg). These effects are not a product of changes in motor coordination or locomotor activity. At α7 nAChRs, DM497 potentiated whereas DM490 inhibited its activity. In addition, DM490 antagonized the α9α10 nAChR with >8-fold higher potency than that for DM497. In contrast, DM497 and DM490 had minimal inhibitory activity at the Ca V 2.2 channel. Considering that DM497 did not increase the mouse exploratory activity, an indirect anxiolytic mechanism was not responsible for the observed antineuropathic effect. The antinociceptive activity of DM497 and the concomitant inhibitory effect of DM490 are mediated by opposing modulatory mechanisms on the α7 nAChR, whereas the involvement of other possible nociception targets such as the α9α10 nAChR and Ca V 2.2 channel can be ruled out.

Age, β-endorphin, and sex dependent effects of maternal separation on locomotor activity, anxiety-like behavior, and alcohol reward.

Childhood adversity is pervasive and linked to numerous disadvantages in adulthood, including physical health problems, mental illness, and substance use disorders. Initial sensitivity to the rewarding effects of alcohol predicts the risk of developing an alcohol use disorder, and may be linked to developmental stress. The opioid peptide β-endorphin (β-E) regulates the stress response and is also implicated in the risk for excessive alcohol consumption. We explored the influence of β-E in an animal model of early life adversity using controlled maternal separation by evaluating changes in locomotor activity, anxiety-like behavior, and the initial rewarding effects of alcohol in a single exposure conditioned place preference paradigm in control C57BL/6J and β-E deficient β-E +/+ 0.129S2-Pomc tm1Low/J; β-E -/- mice. Maternal separation (MS) occurred for 3 h each day from post-natal days (PND) 5-18 in approximately half the subjects. Maternal interactions increased following the separation protocol equally in both genotypes. MS and control subjects were tested as adolescents (PND 26-32) or adults (PND 58-72); the effects of MS were generally more pronounced in older subjects. Adults were more active than adolescents in the open field, and MS decreased activity in adolescent mice but increased it in adults. The increase in adult activity as a result of early life stress depended on both β-E and sex. β-E also influenced the effect of maternal separation on anxiety-like behavior in the Elevated Plus Maze. MS promoted rewarding effects of alcohol in male β-E deficient mice of either age, but had no effect in other groups. Taken together, these results suggest that the effects of MS develop over time and are β-E and sex dependent and may aid understanding of how individual differences influence the impact of adverse childhood experiences.