Swimming Test In Mice Research Articles

Discovery of Multi-functional Lead Compounds Originating from Traditional Chinese Medicine for Developing Anti-depressive Agents via Virtual Screening

Background: The increasing prevalence of depression has become a global health issue. Currently approved anti-depressive including 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), triple reuptake inhibitors (TRIs) and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists have limited effects because of their insufficient efficacy and/or slow onset of action. Developing multifunctional antidepressants that can modulate 5-HT, DA, NE, and NMDA simultaneously can potentially overcome the current drug defects. Objective: This study aimed to explore leads for the development of multi-functional anti-depressive agents that simultaneous triple reuptake inhibitory and NMDA-GluN2B receptor antagonistic activities. Methods: Potential leads were screened virtually from the TCMSP database based on the 3DPharmacophore model of TRIs followed by the molecular docking into NMDA-GluN2B receptor, BBB score, and the in silico toxicity evaluation. The biological activities of discovered leads on 5-HT, NE, and DA reuptake and their effect on the NMDA-GluN2B receptor were evaluated via radio-labeled neurotransmitters and competition radio-ligand binding experiment with [3H] ifenprodil, respectively. Lastly, the antidepressant effect of these potential leads was determined in vivo through the forced swim test in mice. Results: Two compounds were attained as potential leads after the aforementioned experiments. Further in vitro biological evaluation identified Hit-2 as a promising lead that exerted favorable triple 5- HT/DA/NE reuptake inhibitory activity (66.98% inhibition rate at 10 μM against hNET, 73.01% inhibition rate at 1 μM against hDAT and 86.27% inhibition rate at 1 μM against hSERT), as well as potent NMDA-GluN2B receptor antagonistic activity (Ki=115.73 ± 3.54 nM). The antidepressant activity of Hit- 2 was confirmed through in vivo experiments Conclusion: Hit-2 not only simultaneously inhibited the reuptake of 5-HT, DA, and NE, and acted as an NMDA-GluN2B receptor antagonist in vitro but also showed in vivo antidepressant activity. These findings may serve as a structural basis for the further development of multi-functional anti-depressive agents.

Trimethylamine N-Oxide Improves Exercise Performance by Reducing Oxidative Stress through Activation of the Nrf2 Signaling Pathway.

Trimethylamine N-oxide (TMAO) has attracted interest because of its association with cardiovascular disease and diabetes, and evidence for the beneficial effects of TMAO is accumulating. This study investigates the role of TMAO in improving exercise performance and elucidates the underlying molecular mechanisms. Using C2C12 cells, we established an oxidative stress model and administered TMAO treatment. Our results indicate that TMAO significantly protects myoblasts from oxidative stress-induced damage by increasing the expression of Nrf2, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (NQO1), and catalase (CAT). In particular, suppression of Nrf2 resulted in a loss of the protective effects of TMAO and a significant decrease in the expression levels of Nrf2, HO-1, and NQO1. In addition, we evaluated the effects of TMAO in an exhaustive swimming test in mice. TMAO treatment significantly prolonged swimming endurance, increased glutathione and taurine levels, enhanced glutathione peroxidase activity, and increased the expression of Nrf2 and its downstream antioxidant genes, including HO-1, NQO1, and CAT, in skeletal muscle. These findings underscore the potential of TMAO to counteract exercise-induced oxidative stress. This research provides new insights into the ability of TMAO to alleviate exercise-induced oxidative stress via the Nrf2 signaling pathway, providing a valuable framework for the development of sports nutrition supplements aimed at mitigating oxidative stress.

The effect of vine tea (Ampelopsis grossedentata) extract on fatigue alleviation via improving muscle mass

Ethnopharmacological relevanceVine Tea (VT, Ampelopsis grossedentata), boasts a venerable tradition in China, with a recorded consumption history exceeding 1200 years. Predominantly utilized by ethnic groups in southwest China, this herbal tea is celebrated for its multifaceted therapeutic attributes. Traditionally, VT has been employed to alleviate heat and remove toxins, exhibit anti-inflammatory properties, soothe sore throats, lower blood pressure, and fortify bones and muscles. In the realm of functional foods derived from plant resources, VT has garnered attention for its potential in crafting anti-fatigue beverages or foods, attributed to its promising efficacy and minimal side effects. Currently, in accordance with the Food Safety Standards set forth by the Monitoring and Evaluation Department of the National Health and Family Planning Commission in China, VT serves as a raw material in various beverages. Aim of the studyVT has an anti-fatigue or similar effect in folk. However, the underlying molecular mechanisms contributing to VT's anti-fatigue effects remain elusive. This study endeavors to investigate the influence of Vine Tea Aqueous Extract (VTE) on fatigue mitigation and to elucidate its operative mechanisms, with the objective of developing VTE as a functional beverage. Materials and methodsThe preparation of VTE involved heat extraction and freeze-drying processes, followed by the identification of its metabolites using UPLC-QTOF-MS to ascertain the chemical composition of VTE. A fatigue model was established using a forced swimming test in mice. Potential molecular targets were identified through network pharmacology, transcriptome analysis, and molecular docking. Furthermore, RT-PCR and Western blot techniques were employed to assess mRNA and protein expressions related to the AMPK and FoxO pathways. ResultsVTE significantly prolonged the duration of swimming time in an exhaustive swimming test in a dose-dependent manner, while simultaneously reducing the concentrations of blood lactic acid (LA), lactate dehydrogenase (LDH), serum urea nitrogen (SUN), and creatine kinase (CK). Notably, the performance of the high-dose VTE group surpassed that of the well-recognized ginsenoside. VTE demonstrated a regulatory effect akin to ginsenoside on the AMPK energy metabolism pathway and induced downregulation in the expression of Gadd45α, Cdkn1a, FOXO1, and Fbxo32 genes, suggesting an enhancement in skeletal muscle mass. These findings indicate that VTE can improve energy metabolism and muscle mass concurrently. ConclusionsVTE exhibits significant anti-fatigue effects, and its mechanism is intricately linked to the modulation of the AMPK and FoxO pathways. Crucially, no caffeine or other addictive substances with known side effects were detected in VTE. Consequently, vine tea shows substantial promise as a natural resource for the development of anti-fatigue beverages within the food industry.

Broad-spectrum ginsentides are principal bioactives in unraveling the cure-all effects of ginseng

Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum “cure-all” effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's “cure-all” medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with in vitro, ex vivo and in vivo validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway, alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.

Antidepressant activity of the pyrrolo[1,2a][1,4]diazepine GMAL-24 in a forced swimming test in mice

The antidepressant activity of pyrrolo[1,2a][1,4]diazepines (GMAL-24, GMAL-27, GMAL-31, GMAL-32 and GMAL-33) synthesized at the V.V. Zakusov Research Institute of Pharmacology in a forced swimming test on male outbred mice was studied. The compounds were tested in the dose range from 1.5 mg/kg to 20 mg/kg, the reference group received tricyclic antidepressant amitriptyline at a dose of 10 mg/kg, and the control group received 0.5 ml of saline solution. All injections were performed intraperitoneally. After GMAL-27 administration immobilization time was decreased of 1.78, 1.64 and 1.74 times, respectively, compared with the control in all three studied doses (1.5 mg/kg, 5 mg/kg and 10 mg/kg), without significant differences from the control (p = 0.1340; p = 0.2748; p = 0.2214, respectively). The compound GMAL-31 in doses from 1.5 mg/kg to 20 mg/kg had no effect on the duration of immobilization compared to the control group of mice. It was established that the compound GMAL-24 at doses of 5 mg/kg and 10 mg/kg significantly reduced the periods of immobilization compared to the control group and did not differ in this parameter from the comparison drug, which indicates an antidepressant effect comparable to the effect of amitriptyline.

Design and synthesis of a novel dipeptide mimetic of the 4th loop of neurotrophin-3 and its pharmacological effects

A novel neurotrophin-3 loop 4 dipeptide mimetic, bis(N-γ-hydroxybutyryl-L-glutamyl-L-asparagine) hexamethylenedi-amide (GTS-302), was designed and synthesized. Compound GTS-302 activated the tyrosine kinase receptors TrkC and TrkB, exhibited cytoprotective activity (10-8–10-5 M) in oxidative stress model in HT-22 cells and in 6-hydroxy-dopamine-induced SH-SY5Y cell damage. It also demon- strated an antidepressant-like activity in the forced swim test in mice (0.5–10.0 mg kg–1, intraperitoneally).

The study of the spectrum of pharmacological activity of the new original NT-3 mimetic dipeptide GTS-302

BACKGROUND: The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with the deficit of neurotrophin-3 determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-size neurotrophin-3 is limited by unsatisfactory pharmacokinetic properties, it is relevant to create low-molecular-weight mimetics of neurotrophin-3 that are active when administered systemically. A dimeric dipeptide mimetic of the 4th loop of neurotrophin-3, hexamethylenediamide bis(N--oxibutyryl-L-glutamyl-L-asparagine) GTS-302, which activates TrkC and TrkB receptors, has been developed at the V.V. Zakusov Research Institute of Pharmacology.
 AIM: The aim of this study was to investigate the spectrum of pharmacological activity of GTS-302.
 MATERIALS AND МETHODS: The pharmacological effects of GTS-302 were investigated following its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swim test in mice after acute and 7-day administration. The anxiolytic and cognitive activity of the dipeptide were studied in the elevated plus maze test in mice and the novel object recognition test in rats after acute administration, respectively. The effect of GTS-302 on pain sensitivity was studied in the hot plate test in mice after acute administration.
 RESULTS: It was found that GTS-302 exhibits antidepressant-like activity after acute administration at doses of 0.5, 1.0, 5.0 and 10 mg/kg. After 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of effect size and statistical significance. The dipeptide GTS-302 at doses of 1.0, 5.0 and 10.0 mg/kg showed anxiolytic and cognitive activity and did not affect pain sensitivity.
 CONCLUSIONS: The pharmacological spectrum of the low-molecular-weight mimetic of neurotrophin-3, dipeptide GTS-302, revealed upon systemic administration includes a number of neuropsychotropic effects characteristic of the full-sized neurotrophin. This allows us to consider GTS-302 as a potential neuropsychotropic drug.

The role of GPR39 zinc receptor in the modulation of glutamatergic and GABAergic transmission

BackgroundDespite our poor understanding of the pathophysiology of depression, a growing body of evidence indicates the role of both glutamate and gamma-aminobutyric acid (GABA) signaling behind the effects of rapid-acting antidepressants (RAADs). GPR39 is a zinc-sensing receptor whose activation leads to a prolonged antidepressant-like response in mice. Both GPR39 and zinc can modulate glutamatergic and GABAergic neurotransmission, however, exact molecular mechanisms are still elusive. In this study, we aimed to research the role of glutamatergic and GABAergic system activation in TC-G 1008 antidepressant-like effects and the disruptions in this effect caused by a low-zinc diet.MethodsIn the first part of our study, we investigated the role of joint administration of the GPR39 agonist (TC-G 1008) and ligands of the glutamatergic or GABAergic systems, in antidepressant-like response. To evaluate animal behaviour we used the forced swim test in mice. In the second part of the study, we assessed the effectiveness of TC-G 1008-induced antidepressant-like response in conditions of decreased dietary zinc intake and its molecular underpinning by conducting a Western Blot analysis of selected proteins involved in glutamatergic and GABAergic neurotransmission.ResultsThe TC-G 1008-induced effect was blocked by the administration of NMDA or picrotoxin. The joint administration of TC-G 1008 along with muscimol or SCH50911 showed a trend toward decreased immobility time. Zinc-deficient diet resulted in dysregulation of GluN1, PSD95, and KCC2 protein expression.ConclusionsOur findings indicate the important role of glutamate/GABA signaling in the antidepressant-like effect of TC-G 1008 and imply that GPR39 regulates the balance between excitatory and inhibitory activity in the brain. Thus, we suggest the zinc-sensing receptor be considered an interesting new target for the development of novel antidepressants.

Synergistic anti-depressive effect of combination treatment of Brexpiprazole and selective serotonin reuptake inhibitors on forced swimming test in mice.

Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15min before testing. Escitalopram (10mg/kg), fluoxetine (75 mg/kg), paroxetine (10mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p=0.0411). Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Astragali Radix-Codonopsis Radix-Jujubae Fructus water extracts ameliorate exercise-induced fatigue in mice via modulating gut microbiota and its metabolites.

Astragali Radix (AR) and Codonopsis Radix (CR) are widely used as the tonic herbal medicine with efficacy of tonifying qi in traditional Chinese medicine (TCM), which showed significant antifatigue activities. In this study, AR and CR were combined, with Jujubae Fructus (JF) further added to improve the taste, to afford the ACJ extracts in the ratio of 2:1:2. The results showed that ACJ water extract exhibited antifatigue effect by the weight-loaded exhaustive swimming test in mice. The untargeted fecal metabolomic approach and 16S rRNA gene sequencing analysis showed that ACJ could improve exercise performance by regulating changes of gut metabolites and microbiota to alleviate fatigue. Four pathways were determined as the key pathways relating with its antifatigue effect, which included sphingolipid metabolism, glycerophospholipid metabolism, valine, leucine and isoleucine biosynthesis and d-arginine and d-ornithine metabolism. Correlation analysis showed the complex association among bacteria, metabolites and phenotypes. In conclusion, this study revealed new perspectives to study the antifatigue mechanism of ACJ extracts from the gut microbiota, which provided the basis for further functional food development. © 2022 Society of Chemical Industry.

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease.

Anti-fatigue activity of Brassica rapa L. extract and correlation among biochemical changes in forced swimming mice

Brassica rapa L. is an edible and medical plant in China used for treating various diseases, especially in the Tibet region. In this study, the chemical constituents of Brassica rapa L. extract (BE) was clarified by UHPLC-MS and anti-fatigue ability of BE was assessed through the behavior test and weight-loaded forced swimming test in mice. Then we determined several biochemical parameters related to fatigue to explore possible reasons. Results indicate that BE could significantly enhance exercise performance in mice, and there was a significant improvement in both grip-strength and the time on rota-rods. Meanwhile, BE showed significant anti-fatigue effects by decreasing the blood lactic acid (BLA), blood urea nitrogen (BUN), and creatine kinase (CK) levels and increasing the lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels. Increases in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were observed and reactive oxygen species (ROS) levels was regulated. Liver and muscle glycogen levels and adenosine triphosphate (ATP) levels were also significantly increased. Pearson correlation analysis indicates that fatigue-related indexes including metabolites and energy-related indexes were significantly correlated with antioxidant levels. In conclusion, BE possesses remarkable anti-fatigue activity, thereby shows great potential for improving exercise performance and alleviating physical fatigue and can be considered as a functional food supplement for further development.

Antidepressant-like Effects of BDNF and NGF Individual Loop Dipeptide Mimetics Depend on the Signal Transmission Patterns Associated with Trk.

Neurotrophins are considered as an attractive target for the development of antidepressants with a novel mechanism of action. Previously, the dimeric dipeptide mimetics of individual loops of nerve growth factor, NGF (GK-6, loop 1; GK-2, loop 4) and brain-derived neurotrophic factor, BDNF (GSB-214, loop 1; GTS-201, loop 2; GSB-106, loop 4) were designed and synthesized. All the mimetics of NGF and BDNF in vitro after a 5–180 min incubation in a HT-22 cell culture were able to phosphorylate the tropomyosin-related kinase A (TrkA) or B (TrkB) receptors, respectively, but had different post-receptor signaling patterns. In the present study, we conduct comparative research of the antidepressant-like activity of these mimetics at acute and subchronic administration in the forced swim test in mice. Only the dipeptide GSB-106 that in vitro activates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and phospholipase C-gamma (PLCγ) post-receptor pathways exhibited antidepressant-like activity (0.1 and 1.0 mg/kg, ip) at acute administration. At the same time, the inhibition of any one of these signaling pathways completely prevented the antidepressant-like effects of GSB-106 in the forced swim test. All the NGF mimetics were inactive after a single injection regardless of post-receptor in vitro signaling patterns. All the investigated dipeptides, except GTS-201, not activating PI3K/AKT in vitro unlike the other compounds, were active at subchronic administration. The data obtained demonstrate that the low-molecular weight BDNF mimetic GSB-106 that activates all three main post-receptor TrkB signaling pathways is the most promising for the development as an antidepressant.

Unilateral facial injection of Botulinum neurotoxin A attenuates bilateral trigeminal neuropathic pain and anxiety-like behaviors through inhibition of TLR2-mediated neuroinflammation in mice

ObjectivesIn this study, we investigated the possible analgesic effects of Botulinum toxin type A (BoNT/A) on trigeminal neuralgia (TN). A modified TN mouse model was established by chronic constriction injury of the distal infraorbital nerve (dIoN-CCI) in mice, and the possible roles of microglia toll-like receptor 2 (TLR2) and neuroinflammation was investigated.MethodsMale C57BL/6 mice were divided into 3 groups, including sham group, vehicle-treated TN group and BoNT/A-treated TN group. Bilateral mechanical pain hypersensitivity, anxiety-like and depressive-like behaviors were evaluated by using von Frey test, open field, elevated plus-maze testing, and forced swimming test in mice, respectively. The mRNA or protein expression levels of toll-like receptors (TLRs), glia activation markers and proinflammatory factors in the trigeminal nucleus caudalis (TNC) were tested by RT-qPCR, immunofluorescence and Western blotting. We also tested the pain behaviors of TN in Tlr2−/− mice.ResultsWe found that unilateral subcutaneous injection of BoNT/A into the whisker pad on the ipsilateral side of dIoN-CCI mice significantly attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors induced by dIoN-CCI surgery in mice. The dIoN-CCI surgery significantly up-regulated the expression of TLR2, MyD88, CD11b (a microglia marker), IL-1β, TNF-α and IL-6 in the ipsilateral TNC in mice, and BoNT/A injection significantly inhibited the expression of these factors. Immunostaining results confirmed that BoNT/A injection significantly inhibited the microglia activation in the ipsilateral TNC in dIoN-CCI mice. TLR2 deficiency also alleviated bilateral mechanical pain hypersensitivity and the up-regulation of MyD88 expression in the TNC of dIoN-CCI mice.ConclusionThese results indicate that unilateral injection of BoNT/A attenuated bilateral mechanical pain hypersensitivity and anxiety-like behaviors in dIoN-CCI mice, and the analgesic effects of BoNT/A may be associated with the inhibition of TLR2-mediated neuroinflammation in the TNC.

Evaluation of anti-fatigue property of Porphyridium cruentum in mice

Purpose: To evaluate the potential effects of Porphyridium cruentum (PC) on fatigue induced by forced swimming test in mice.
 Methods: Mice were randomly divided into normal control group (NC, i.e., untreated non-swimming); model control group (MC, untreated swimming); Spirulina treated group (SP, 800 mg/kg); PC-treated groups (50, 100, and 200 mg/kg), respectively. After intragastric administration for 14 consecutive days, a weight-bearing swimming experiment was conducted for the mice, and the biochemical indicators related to fatigue were examined, including exhaustive swimming time, glucose levels (Glu), hepatic glycogen contents (HG), muscle glycogen contents (MG), glutathione peroxidase activities (GSH-Px), creatine kinase (CK), malondialdehyde (MDA), urea nitrogen levels (SUN), lactate dehydrogenase activities (LDH), lactic acid (LA) as well as superoxide dismutase (SOD).
 Results: PC significantly prolonged the swimming endurance time compared to MC. After PC treatment, Glu, HG and MG were effectively increased dose-dependently, SUN, LA, LDH and CK levels in serum were significantly reduced. Moreover, PC treatment elevated the bioactivities of two antioxidant enzymes, namely, GSH-Px and SOD, while MDA content decreased when compared to MC group.
 Conclusion: These results indicate that PC exhibits strong anti-fatigue effect. Thus, PC may be suitable for incorporation in functional food to counter fatigue.

Tibetan Medicine Duoxuekang Capsule Ameliorates High-Altitude Polycythemia Accompanied by Brain Injury.

Objective: Duoxuekang (DXK) capsule is an empirical prescription for Tibetan medicine in the treatment of hypobaric hypoxia (HH)-induced brain injury in the plateau. This study aimed to investigate the protective effects and underlying molecular mechanisms of DXK on HH-induced brain injury. Methods: UPLC–Q-TOF/MS was performed for chemical composition analysis of DXK. The anti-hypoxia and anti-fatigue effects of DXK were evaluated by the normobaric hypoxia test, sodium nitrite toxicosis test, and weight-loaded swimming test in mice. Simultaneously, SD rats were used for the chronic hypobaric hypoxia (CHH) test. RBC, HGB, HCT, and the whole blood viscosity were evaluated. The activities of SOD and MDA in the brain, and EPO and LDH levels in the kidney were detected using ELISA. H&E staining was employed to observe the pathological morphology in the hippocampus and cortex of rats. Furthermore, immunofluorescence and Western blot were carried out to detect the protein expressions of Mapk10, RASGRF1, RASA3, Ras, and IGF-IR in the brain of rats. Besides, BALB/c mice were used for acute hypobaric hypoxia (AHH) test, and Western blot was employed to detect the protein expression of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 in the cerebral cortex of mice. Results: 23 different chemical compositions of DXK were identified by UPLC–Q-TOF/MS. The anti-hypoxia test verified that DXK can prolong the survival time of mice. The anti-fatigue test confirmed that DXK can prolong the swimming time of mice, decrease the level of LDH, and increase the hepatic glycogen level. Synchronously, DXK can decrease the levels of RBC, HGB, HCT, and the whole blood viscosity under the CHH condition. Besides, DXK can ameliorate CHH-induced brain injury, decrease the levels of EPO and LDH in the kidney, reduce MDA, and increase SOD in the hippocampus. Furthermore, DXK can converse HH-induced marked increase of Mapk10, RASGRF1, and RASA3, and decrease of Ras and IGF-IR. In addition, DXK can suppress the ratio of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 under the HH condition. Conclusion: Together, the cerebral protection elicited by DXK was due to the decrease of hematological index, suppressing EPO, by affecting the MAPK signaling pathway in oxidative damage, and regulating the RAS signaling pathway.

Preferential Effect of Loxoprofen in Lipopolysaccharide Induced Immobility-Time in Forced Swim Test in Mice

Preferential Effect of Loxoprofen in Lipopolysaccharide Induced Immobility-Time in Forced Swim Test in Mice

Low-Molecular Weight BDNF Mimetic, Dimeric Dipeptide GSB-106, Reverses Depressive Symptoms in Mouse Chronic Social Defeat Stress.

A mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, named GSB-106, was designed and synthesized in our scientific group. The compound activated TrkB, MAPK/ERK, PI3K/AKT, and PLCγ in in vitro experiments. In vivo experiments with rodents revealed its antidepressant-like activity in the forced swim and the tail suspension tests at the dose range of 0.1–5.0 mg/kg (i.p., p.o.). However, GSB-106 was not studied in depression models modulating major depression in humans. In the present study, the GSB-106 antidepressant-like activity was revealed in mice at the depression model induced by 28-day social defeat stress with 21-days oral administration (0.1 mg/kg) after stress. At the same time, GSB-106 restored reduced locomotor activity and completely eliminated the anhedonia manifestations. The compound also restored reduced levels of synaptophysin and CREB in the hippocampus. In addition, the Trk receptor antagonist K252A, and the PLC inhibitor U73122, were found to completely block the antidepressant-like activity of GSB-106 in the forced swimming test in mice. Thus, the present results demonstrate the dipeptide BDNF mimetic GSB-106 reversed depressive-like behavior and restored hippocampal neuroplasticity in a rodent depression model. These effects of GSB-106 are probably regulated by TrkB signaling.

ASSESSMENT OF NEUROPROTECTIVE EFFECTS OF ALKALOID COMPOUNDS

Beta-carboline alkaloids show a wide range of psychopharmacological effects (for example, some beta-carboline alkaloids facilitate dopaminergic transmission and interact with dopaminergic receptors D1 and D2 in the striatum). This article presents data on neuroprotective effects of alkaloid compounds using computer simulation methods, docking-based virtual screening, and experimental pharmacology. The purpose of the study was to investigate the neuroprotective/stress-protective action of new derivatives of alkaloid compounds using the methods of computer simulation, docking-based virtual screening, and experimental pharmacology. Through ChemDraw, MGLTools programs, they have used computer modeling of the molecules of alkaloid derivatives, docking-based virtual screening, DRD2 receptor, and three-dimensional models of the ligand molecules. The binding energy of an individual conformation was used as a final result, which shows the strength of the interaction between the ligand and the target molecule. 22 compounds of alkaloids and their derivatives were studied. Virtual molecule modeling was performed for compounds and receptors, “ligand-target” molecule docking was carried out, and candidate compounds were selected. In vivo experimental studies of the neuroprotective effects of these compounds were conducted in the emotional stress model. The effects of harmine, norharmane, and guanine alkaloids on immobility time in the forced swimming test in mice, a model of depression in animals, were studied. A forced swimming test and an elevated plus-maze were used to determine the antidepressant and anxiolytic effects of harmine in rats. According to the docking results, the presented molecules of alkaloid compounds showed interactions with dopamine receptorD2. The results obtained in the “Elevated Plus Maze” test showed that the animals treated with 9-methoxy-2-phenyl-11H-indolisino[8,7-β]indole, lappaconitine and cytisine at a dose of 5 mg/kg, compared to rats in the control group, experienced an anxiolytic (anti-anxiety) actionin the experimental emotional stress.

Irisin ameliorates the postoperative depressive-like behavior by reducing the surface expression of epidermal growth factor receptor in mice

Postoperative depression is a serious problem with under-optimized treatment. Our previous result demonstrated that single dose of propofol exposure in mice could cause depressive-like behavior. In the present study, we explored the possible preventive strategy that could ameliorate the depressive-like behavior in mice. Irisin was used for co-treatment with propofol in mice to test whether irisin could prevent the depressive-like behavior in mice. We found irisin could significantly reduce the immobility time in tail suspension and forced swimming tests in mice with propofol. We also found irisin was able to protect neurons against high concentration propofol treatment induced cell death in cultures. Meanwhile, irisin could significantly inhibit the increase of cytokines in astrocyte cultures exposed to propofol. These in vitro results suggested that interaction between astrocyte and neuron may be involved in the action mechanism that irisin prevented the mice from developing of depressive-like behavior. Last, we revealed that propofol caused increased surface expression of epidermal growth factor receptor (EGFR) but irisin could reduce the expression level of EGFR on cell surface.