Ispitivanje antidepresivnog, sedativnog i analgetskog djelovanja novih fuzioniranih derivata tiofena

This study was aimed at the synthesis of fused benzothiophene derivatives containing heterocyclic moiety. The reaction of the tetrahydrobenzo[b]thiophene derivatives 1a,b with ethoxycarbonylisothiocyanate afforded the thiourea derivatives 2a,b. Cyclization of the latter products gave the annulated benzo[b]thienopyrimidine derivatives 3a,b. Compounds 2a,b and 3a underwent a series of heterocyclization reactions through the reaction with some chemical reagents to give the new benzo[b]thienopyrimidine derivatives 5a,b to 8a-c. Also, this work was extended to study the potential role of the novel synthesized thiourea derivative 2a and benzo[b]thienopyrimidine derivatives 3a, 5b, 6a and 8b as antidepressant, sedative or analgesic agents at two doses (15 or 30 mg kg1 body mass). Some compounds (2a, 3a and 5b) showed mild antidepressant activity in the forced-swimming test. No compound showed sedative effect. Visceral pain evoked by i.p. injection of acetic acid in mice was significantly inhibited by all compounds at a high doses.U radu je opisana sinteza fuzioniranih derivata benzotiofena koji sadrže heterociklički ostatak bitan za farmakološko djelovanje. Tiourea derivati 2a,b dobiveni su reakcijom derivata tetrahidrobenzo[b]tiofena 1a,b s etoksikarbonilizotiocijanatom. Iz njih su dalje priređeni anulirani derivati benzo[b]tienopirimidina 3a,b. Spojevi 2a,b i 3a prevedeni su reakcijama heterociklizacije u benzo[b]tienopirimidine 5a,b-8a-c. Ispitivano je antidepresivno, sedativno i analgetsko djelovanje novosintetiziranih derivata tiouree 2a i benzo[b]tienopirimidina 3a, 5b, 6a i 8b u dvije doze (15 ili 30 mg kg1 tjelesne mase). Spojevi 2a, 3a i 5b pokazali su blago antidepresivno djelovanje u testu forsiranog plivanja, dok sedativni učinak nije pokazao niti jedan ispitivani spoj. Visceralna bol inducirana i.p. injekcijom octene kiseline u miševa značajno je inhibirana sa svim spojevima, ali u visokim dozama

Day and night: diurnal phase influences the response to chronic mild stress

Chronic mild stress (CMS) protocols are widely used to create animal models of depression. Despite this, the inconsistencies in the reported effects may be indicative of crucial differences in methodology. Here, we considered the time of the diurnal cycle in which stressors are applied as a possible relevant temporal variable underlying the association between stress and behavior. Most laboratories test behavior during the light phase of the diurnal cycle, which corresponds to the animal's resting period. Here, rats stressed either in their resting (light phase) or active (dark phase) periods were behaviorally characterized in the light phase. When exposure to CMS occurred during the light phase of the day cycle, rats displayed signs of depressive and anxiety-related behaviors. This phenotype was not observed when CMS was applied during the dark (active) period. Interestingly, although no differences in spatial and reference memory were detected (Morris water maze) in animals in either stress period, those stressed in the light phase showed marked impairments in the probe test. These animals also showed significant dendritic atrophy in the hippocampal dentate granule neurons, with a decrease in the number of spines. Taken together, the observations reported demonstrate that the time in which stress is applied has differential effects on behavioral and neurostructural phenotypes.Shilan Aslani and Mazen R. Harb were supported by EU Marie Curie Initial Training Fellowships from the NINA Project. Part of this work was supported by the Life and Health Sciences Research Institute (ICVS) and by FEDER funds through Operational program for competitivity factors-COMPETE and by national funds through FCT-Foundation for Science and Technology to project "PTDC/SAU-NSC/111814/2009.

Dopamine neurons modulate neural encoding and expression of depression-related behaviour

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry

Comparison of Therapeutic Effects between Pulsed and Continuous Wave 810-nm Wavelength Laser Irradiation for Traumatic Brain Injury in Mice

Background and Objective Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI. Study Design/Materials and Methods TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm2 for 12-minutes giving a fluence of 36-J/cm2. Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test. Results The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests. Conclusion The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT.National Institutes of Health (U.S.) (NIH grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense. Congressionally Directed Medical Research Programs (W81XWH-09-1-0514)United States. Air Force Office of Scientific Research (Military Photomedicine Program (FA9950-04-1-0079))Japan. Ministry of Education, Culture, Sports, Science and TechnologyJapan Society for the Promotion of Scienc

Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice

<p>Abstract</p> <p>Background</p> <p>Extracts of <it>Hypericum perforatum </it>(St. John's wort) have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone administration.</p> <p>Methods</p> <p>CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF), Novelty-Suppressed Feeding (NSF), Forced Swim Test (FST) were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by both 5-bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg) has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined.</p> <p>Results</p> <p>The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration.</p> <p>Conclusion</p> <p>These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment.</p

A New Anti-Depressive Strategy for the Elderly: Ablation of FKBP5/FKBP51

The gene FKBP5 codes for FKBP51, a co-chaperone protein of the Hsp90 complex that increases with age. Through its association with Hsp90, FKBP51 regulates the glucocorticoid receptor (GR). Single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased recurrence of depressive episodes, increased susceptibility to post-traumatic stress disorder, bipolar disorder, attempt of suicide, and major depressive disorder in HIV patients. Variation in one of these SNPs correlates with increased levels of FKBP51. FKBP51 is also increased in HIV patients. Moreover, increases in FKBP51 in the amygdala produce an anxiety phenotype in mice. Therefore, we tested the behavioral consequences of FKBP5 deletion in aged mice. Similar to that of naïve animals treated with classical antidepressants FKBP5−/− mice showed antidepressant behavior without affecting cognition and other basic motor functions. Reduced corticosterone levels following stress accompanied these observed effects on depression. Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies

Evaluation of behavioural and antioxidant activity of Cytisus scoparius Link in rats exposed to chronic unpredictable mild stress

<p>Abstract</p> <p>Background</p> <p>Various human diseases have oxidative stress as one of their component. Many herbs have been reported to exhibit properties that combat oxidative stress through their active constituents such as flavonoids, tannins, phenolic compounds etc. <it>Cytisus scoparius </it>(CS) Link, (Family: Leguminosae), also called <it>Sarothamnus scoparius</it>, has been shown in <it>invitro </it>experiments to be endowed with anti-diabetic, hypnotic and sedative and antioxidant activity. Therefore this study was carried out to evaluate CS for its anxiolytic, antidepressant and anti-oxidant activity in stressed rats.</p> <p>Methods</p> <p>60% methanolic extract of CS was quantified for phenolic content by Folin-Ciocalteau's method. Chronic unpredictable mild stress (CMS) was employed to induce stress in rats. CS (125 and 250 mg/kg, p.o) and diazepam (DZM) (2 mg/kg, p.o) was administered during the 21 day stress exposure period. Anxiolytic and antidepressant activities of CS were assessed in open field exploratory and behavioural despair paradigms, respectively. Plasma glucose and total lipids; endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT); non-enzymic-ascorbic acid and thiobarbituric acid reactive substances (TBARS) levels were measured in brain, kidneys and adrenals using standard protocols to assess the effect of CS.</p> <p>Results</p> <p>Total phenolic content of CS was found to be 8.54 ± 0.16% w/w. CMS produced anxiogenic and depressive behaviour in experimental rats with metabolic disturbance. Significant decrease in SOD, CAT levels and increase in lipid peroxidation level was observed in stressed rats. CS administration for 21 days during stress exposure significantly increased the ambulatory behaviour and decreased the freezing time in open field behaviour. In behavioural despair test no significant alteration in the immobility period was observed. CS also improved SOD, CAT, and ascorbic acid level and controlled the lipid peroxidation in different tissues.</p> <p>Conclusion</p> <p>CS possesses anti-stress and moderate anxiolytic activity which may be due, in part, to its antioxidant effect that might warrant further studies.</p

The Effects of Breeding Protocol in C57BL/6J Mice on Adult Offspring Behaviour

Animal experiments have demonstrated that a wide range of prenatal exposures can impact on the behaviour of the offspring. However, there is a lack of evidence as to whether the duration of sire exposure could affect such outcomes. We compared two widely used methods for breeding offspring for behavioural studies. The first involved housing male and female C57Bl/6J mice together for a period of time (usually 10–12 days) and checking for pregnancy by the presence of a distended abdomen (Pair-housed; PH). The second involved daily introduction of female breeders to the male homecage followed by daily checks for pregnancy by the presence of vaginal plugs (Time-mated; TM). Male and female offspring were tested at 10 weeks of age on a behavioural test battery including the elevated plus-maze, hole board, light/dark emergence, forced swim test, novelty-suppressed feeding, active avoidance and extinction, tests for nociception and for prepulse inhibition (PPI) of the acoustic startle response. We found that length of sire exposure (LSE) had no significant effects on offspring behaviour, suggesting that the two breeding protocols do not differentially affect the behavioural outcomes of interest. The absence of LSE effects on the selected variables examined does not detract from the relevance of this study. Information regarding the potential influences of breeding protocol is not only absent from the literature, but also likely to be of particular interest to researchers studying the influence of prenatal manipulations on adult behaviour