Depressive-Like Behavior Induced by Long-Term Ouabain Administration Accompanied Alteration in Neuroinflammation Parameters in Rats

Objective: The present study aims to investigate the effects of Lithium (Li) on manic- and depressive-like behaviors and inflammatory parameters in rats submitted to the bipolar disorder (BD) model induced by ouabain (OUA). Material and methods: Adult male rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (aCSF). On the fourth day after the ICV injection, the rats received intraperitoneal injections of saline (NaCl 0.9%) or Li (47.5 mg/kg), two times a day, for 14 days. On the seventh day after OUA injection, the locomotor activity was assessed (open field test), and on the fourteenth day, locomotion was evaluated again, which was followed by the forced swimming test to evaluate depressive-like behavior. After euthanasia, inflammatory parameters were evaluated in the frontal cortex and hippocampus. Results: After seven days of OUA administration, the animals showed a hyperactive behavior that was reversed by treatment with Li. After 14 days of ICV injections, rats exhibited a depressive behavior. Regarding the inflammatory parameters, measured after 14 days of the ICV infusions, OAU induced an increase in the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor α, and cytokine-induced neutrophil chemoattractant-1. In contrast, Li treatment decreased these parameters. Conclusion: The animal model of BD induced by an OUA is able to induce neuroinflammation, which supports its construct validity for the BD research.

Analysis of the effects of caffeine and dioxidine on biochemical indicators of blood in mouse

Relevance . In connection with the widespread use of caffeine, an important issue is the study of its interaction with substances that can exhibit toxic effects. Objective. The aim of the study is to assess the degree of influence of caffeine and dioxidine on the biochemical parameters of blood in mice in the forced swimming test. Materials and methods. The studies were carried out on 6 groups of male mice: control and five experimental. During 15 days of the experiment, the animals of the control group were injected with physiological saline, and the experimental animals were injected with caffeine at a dose of 40 mg/kg or 100 mg/kg (1 and 2), dioxidine in an amount of 200 mg/kg (3), and caffeine was combined and dioxidine (4 and 5). Biochemical parameters were used to determine the content of glucose, cholesterol, urea, creatinine, the activity of aspartic and alanine aminotransferases. Results . The introduction of caffeine at a dose of 40 mg/kg led to a decrease in glucose levels below normal and an increase in cholesterol and urea concentrations. The use of caffeine at a dose of 100 mg/ kg caused a decrease in glucose levels below normal and an increase in urea concentration. With the introduction of dioxidine at a dose of 200 mg/kg, an increase in the level of glucose, cholesterol, urea, as well as the activity of AST and ALT was taken. The combined use of caffeine and dioxidine by the 15th day led to 100 % mortality in experimental animals. Conclusions . The results of the experiment indicate that the introduction of caffeine at a dose of 40 mg/kg and 100 mg/kg leads to an increase in most of the measured parameters relative to the control values, but they do not go beyond normal values, however, a decrease in glucose levels is noted. These changes in indicators are due to the predominance of catabolic processes over anabolic ones. In animals treated with dioxidine, a significant increase in the concentration of metabolites and the activity of blood enzymes was found, especially an increase in AST and ALT was noted, which indicates a predominant lesion of cardiomyocytes. The mortality rate of the experimental groups receiving caffeine and dioxidine together by the last day of the experiment is due to the action of an excessive stress factor leading to the depletion of the adaptive capabilities of the organism and the death of experimental animals.

Effects of Terazosin, Silodosin and Alfuzosin on Depression and Anxiety in Mice

Aims: Benign prostatic hyperplasia (BPH) is common urological disease, is characterized by lower urinary tract syndrome, usually associated with sexual dysfunctions. The aim of present study is to investigate the effects of terazosin, silodosin and alfuzosin which are the main treatment options for BPH on depression and anxiety to understand whether these drugs may be effective in BPH caused mood disorders. Study Design: All the drugs were given intraperitoneally (i.p.) in a volume of 0.1 ml per 10 g body weight of mice. Drugs were given 30 min before the experiment. We investigated the effects of terazosin, silodosin and alfuzosin on depression and anxiety, in mice. Place and Duration of Study: Sample: Department of Pharmacology and Department of Urology, Sakarya University, Animal Research Center, between June 2019 and September 2020. Methodology: Here, we examined the effects of terazosin (0.5, 1, 2 mg/kg), silodosin silodosin (1, 3, 10 mg/kg) and alfuzosin (3, 6 and 9 mg/kg) on depression and anxiety by using forced swimming test and elevated plus maze test, respectively, in mice (n:96). Additionally, the locomotor activity was evaluated by open field test. Results: All doses of terazosin, alfuzosin and silodosin significantly increased immobility time, compared to saline group. Silodosin and alfuzosin prolonged the time spent in open arms but terazosin decreased the time spent in open arms compared to saline group. Terazosin, silodosin (1 and 3 mg/kg) and alfuzosin (3 and 6 mg/kg) did not have any effect on the number of entries into the open arms while silodosin (10 mg/kg) and alfuzosin (9 mg/kg) increased the number of entries into open arms. Conclusion: We found that silodosin and alfuzosin had antidepressant and anxiolytic-like effects, while terazosin had depressant and anxiogenic effects. Patients with BPH who need antidepressant and anxiolytic treatment can be treated with a single drug instead of multiple medications.

Electrolytic lesions of the bilateral ventrolateral orbital cortex not only directly reduce depression-like behavior but also decreased desperate behavior induced by chronic unpredicted mild stress in rats

Background Previous studies have revealed that ventrolateral orbital cortex (VLO) may play an important role in the regulation of emotional behavior. However, it is not known what effect VLO damage will have on emotion regulation. Results Data showed that damage of VLO increased the anxiety-like behavior in open field test and elevated plus maze, and decreased the depressive behavior in forced swimming test and learned helplessness test. Besides, the impulsive aggressive behaviors were also increased while the attack latency decreased after VLO lesion. What’s more, damage of VLO decreased depressive behaviors induced by chronic unpredicted mild stress in rats. Conclusions These results suggest that the integrity of VLO plays an important role in emotional regulation, and the damage of VLO may inhibit the development of depression-like behavior.

Xanthine Oxidoreductase Inhibitors Suppress the Onset of Exercise-induced AKI in High HPRT Activity Urat1-Uox Double Knockout Mice

Background Hereditary renal hypouricemia type-1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced acute kidney injury (EIAKI). Because, however, there is no useful experimental RHUC1 animal model, the precise pathophysiological mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI as well as the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). Methods The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. ResultsUrat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine (Cr) and blood urea nitrogen (BUN) as renal injury markers, and decreased Cr clearance (CLCr) observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase (NKA) protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. ConclusionsUrat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1β via NLRP3 inflammasome signaling and NKA dysfunction associated with excessive urinary UA excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

ANTI-PARKINSONIAN ACTIVITY OF VARIOUS SOLVENT EXTRACTS OF CLEOME GYNANDRA LEAVES AGAINST MPTP AND ISOLATION OF PHYTOCONSTITUENTS

Antiparkinsonian activity of Cleome gynandra (CG) was evaluated and chemical constituents were isolated. The results of the present study showed that spontaneous motor activity, retention time and number of head drippings were decreased, whereas immobility time in Tail suspension (TST) and Forced swimming test (FST) were increased in MPTP treated animals, while they were significantly (P<0.001) increased and (P<0.01) decreased with various extracts of CG. Dopamine, serotonin (P<0.001), epinephrine (P<0.01) and glutathione levels were significantly decreased and lipid peroxidation was increased in MPTP treated groups, while their levels were significantly (P<0.001) increased and decreased with various extracts of CG in a dose dependant manner as compared to MPTP, L-dopamine and control groups. Ethanolic leaf extract of CG leads to isolation of triterpenoid, flavone and anthocyanidin - O- methylated flavonoids, which were characterized by using spectroscopic investigation methods like FTIR, NMR and MS.

Pulsed Radiofrequency Upregulates Serotonin Transporters and Alleviates Neuropathic Pain-Induced Depression in a Spared Nerve Injury Rat Model

Neuropathic pain (NP) is difficult to treat due to complex pathophysiological mechanisms. Pulsed radiofrequency (RRF) has been used widely with neuromodulation effect in refractory chronic pain treatment. A recent study found that PRF treatment may decrease chronic pain-related anxiety-depressant symptoms in patients, even though the mechanisms are unclear. Additionally, accumulated evidence has shown serotonin uptake is correlated with various neuropsychiatric diseases. Therefore, we investigated the effects and underlying mechanisms of PRF on depression-like behaviors, resulting from spared nerve injury (SNI)-induced NP. We examined the indexes of mechanical allodynia, cold allodynia, depression-like behavior, and blood cytokines by dynamic plantar aesthesiometry, acetone spray test, forced swimming test, and ProcartaPlex multiplex immunoassays in male Wistar rats, respectively. Serotonin transporters (SERTs) in rat brains were examined by using 4-[18F]-ADAM/PET imaging. We found that specific uptake ratios (SURs) of SERTs were significantly decreased in the brain regions of the thalamus and striatum in rats with SNI-induced NP and depression-like behaviors. Additionally, the decrease in SERT density was correlated with the development of a depression-like behavior indicated by the forced swimming test results and pronounced IL-6 cytokines. Moreover, we demonstrated that PRF application could modulate the descending serotoninergic pathway to relieve pain and depression behaviors.

Synthesis and pharmacological evaluation of novel naphthoquinone derivatives containing 1,2,4-triazine and 1,2,4-triazole moieties of methylene blue on the surface of a "core–shell" type catalyst for the Fenton system

Novel naphthoquinone derivatives bearing 1,2,4-triazine- (4a–b) and 1,2,4-triazole (5a–e) pharmacophores have been synthesized; their structure was confirmed by electrospray ionization mass spectrometry, 1H NMR, 13C NMR, IR spectroscopies and elemental analysis. The obtained heterocyclic compounds were estimated for their anticonvulsant activity on models of chemical- and electrical-induced seizures in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, respectively. Forced swimming test was used to evaluate the antidepressant effect of the naphthoquinone derivatives under study. Compounds 4a–b and 5a–e (100 mg kg–1) demonstrated anticonvulsant action comparable with valproic acid in PTZ-test and prevented the death of 100% of mice in MES model at 3 h and 24 h after oral administration. Moreover, these derivatives showed prolonged antidepressant-like properties, significantly reducing the duration of immobility time in comparison with the reference drug amitriptyline.

Anxiogenic and anxiolytic effects of memantine injected into the ventral hippocampus in male stressed mice

Objectives The effects of intra-ventral hippocampal memantine administration in male NMRI stressed mice were studied. Methods Two stainless steel gauge 23 guide cannulas were placed in the middle part of the mice ventral hippocampus using stereotaxic coordination. Seven days later, the animals were undergone to the stress protocol as follows: They experience four consecutive electro-foot shock stress sessions lasting for 10 min. Five or 30 min before each stress session, the animals received intra-ventral hippocampal (0.1, 1 and, 5 µg/mouse) or intraperitoneal (1, 5, and 10 mg/kg) memantine respectively. Eight days after stress termination, the animals were tested either for the maintenance of either anxiety (elevated plus maze) or depression (forced swimming test). Results Animals show anxiety eight days after stress termination. Intra-ventral hippocampal infusion of memantine (5 µg/mouse) 5 min before stress inhibited the anxiety-like behaviors. However, other doses of the drug exacerbate the stress effect. The drug, when injected peripherally exacerbated the stress effect in all doses. The drug by itself had no effect. In addition, animals also show depression nine days after stress termination and memantine (0.1, 1, and 5 µg/mouse) reduced the stress effect. The drug (0.1 µg/mouse) by itself induced depression in the animals. However, the drug when injected peripherally reduced the stress effect in all doses. Conclusions It could be concluded that NMDA glutamate receptors in the ventral hippocampus may play a pivotal role in the mediation of maintenance of anxiety and depression induced by stress in the mice.

Alpha-terpineol: evaluation and pharmacological screening as an antidepressant agent

Objective: To evaluate the possible antidepressant effects of alpha-terpineol in rodents. Material and Methods: Depression levels were analyzed by comparing the total immobility time presented by the animals of the experimental groups in the test session, using the Forced Swimming Test and the Tail Suspension Test. The parameters of locomotion (central, peripheral and total) and motor coordination were evaluated in the Open Field Test and in the Rota Rod Test, respectively. In the second stage, the involvement of the noradrenergic system in the antidepressant action of alpha-terpineol in Forced Swimming Test was investigated. Results and Discussion: After performing the experimental tests, it was observed that the animals that received alpha-terpineol had reduced immobility time in Forced Swimming Test and Tail Suspension Test, compared to the other groups. In the Open Field Test and Rota-rod, the mice showed, respectively, good exploratory activity and motor coordination during the tests. In addition, the study of the Noradrenergic System proved to be a promising mechanism used during its antidepressant action. Conclusion: In view of the results of the experimental tests, alpha-terpineol presented similar responses to those found in other monoterpenes investigated in the literature. Thus, it is shown as a promising antidepressant to be used clinically in humans, with less side effects and low production cost.