Search

Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored. Impact accelerated TBI by weight drop method causes depression-like behavioral deficits in modified open field exploration, hyper-emotionality and sucrose consumption paradigms. TBI not only causes immediate mechanical damage to the brain, but also induces biochemical changes that lead to delayed neural cell loss leading to a secondary injury. The present study examines the antidepressant effects of ETZ on the TBI-induced depression-like behavior deficits and attempts to explore the underlying mechanism. In order to understand the underlying pathology of TBI and mechanism(s) of ETZ in TBI molecular markers namely, brain cAMP, cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were estimated. Additionally, the level of oxidative (lipid peroxidation) & nitrosative (nitrite) stress markers, along with antioxidant enzymes markers, such as, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured. Furthermore, the involvement of hypothalamic-pituitary adrenal (HPA) axis activity in underlying mechanism was also investigated by measuring serum corticosterone (CORT) level. The results revealed that TBI significantly altered cAMP, pCREB and BDNF levels. Moreover, a significant increase in oxidative–nitrosative stress markers levels, while, significant decreases in antioxidant enzymes markers level were observed. However, no significant change was observed in serum CORT level. Chronic ETZ (0.5 and 1 mg/kg) treatment significantly attenuated TBI-induced behavioral deficits and restored the TBI induced derangements in molecular and biochemical markers. This study indicates that ETZ modulates cAMP signaling and oxidative/antioxidant markers in the TBI model suggesting its prospect as a potential candidate for the pharmacotherapy of depression.

Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention. The present study investigates the effect of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on several pathogenic markers of depression associated with obesity such as plasma insulin resistance, hippocampal cyclic adenosine monophosphate (cAMP), brain-derived neurotrophic factor (BDNF), serotonin (5-HT) concentrations, hippocampal neuronal damage, and p53 protein expression in high-fat-diet (HFD)-fed mice. Obesity was experimentally induced in mice by feeding with HFD for 14 weeks followed by administration of QCM-4 (1 and 2 mg/kg, p.o.)/standard escitalopram (ESC) (10 mg/kg, p.o.)/vehicle (10 ml/kg, p.o.) for 28 days. Behavioral assays such as sucrose preference test (SPT); forced swim test (FST); elevated plus maze (EPM); biochemical assays including oral glucose tolerance tests (OGTT), insulin, cAMP, BDNF, and 5-HT concentrations; and molecular assays mainly histology and immunohistochemistry (IHC) of p53 protein in the dentate gyrus (DG), CA1, and CA3 regions of hippocampus in HFD fed mice were performed. Chronic treatment with QCM-4 in HFD-fed mice reversed the behavioral alterations in SPT, FST, and EPM. QCM-4 showed poor sensitivity for plasma glucose, improved insulin sensitivity, increased hippocampal cAMP, BDNF, and 5-HT concentrations. In the hippocampal DG, CA1, and CA3 regions, QCM-4 treatment improved the neuronal morphology in the histopathology and inhibited p53 protein expression in IHC assay in HFD-fed mice. QCM-4 attenuated the depressive-like phenotype in HFD-fed mice by improving behavioral, biochemical, and molecular alterations through serotonergic neuromodulation.

Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARγ) agonist belonging to thiazolidinedione class, is mainly used in diabetes mellitus. Obese subjects are twice likely to become depressed than non-obese individuals. The biological mechanisms linking depression with obesity still remain poorly understood and there is immense need for better therapeutic intervention against such co-morbid disorders. The present study investigates the effect of pioglitazone on the chronic unpredictable mild stress (CUMS) induced depression in obese mice by using behavioral tests and biochemical estimations. Mice were fed with high fat diet (HFD) for 14 weeks and were further subjected to different stress procedures for 28 days to induce depressive behavior. Animals were administered orally with pioglitazone (30 mg/kg p.o.)/escitalopram (10 mg/kg p.o.)/vehicle (10 ml/kg p.o.) daily from day 15–28. Various behavioral paradigms such as sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM) were performed. Biochemical estimations including plasma glucose, total cholesterol, triglycerides, and total proteins were performed. The data obtained from behavioral assays and biochemical assessments indicated that obese animals exhibited severe depressive-like behavior compared to non-obese animals. Furthermore, obese animals subjected to CUMS worsen the depressive behavior compared to obese control animals. Repetitive treatment with pioglitazone reversed the CUMS induced behavioral and biochemical alterations in HFD fed obese mice which atleast in part may be mediated through improving altered plasma glucose. The study suggests that pioglitazone needs further attention with respect to molecular mechanisms that could provide a better therapeutic strategy against depression associated with obesity., Graphical abstract, Highlights • Obese animals subjected to chronic stress worsens depressive symptoms. • Altered plasma glucose involved in depression co-morbid with obesity. • Pioglitazone inhibited behavioral alterations in obese mice subjected to stress. • Pioglitazone attenuated the biochemical changes in obese mice subjected to stress. • Antidepressant-like effect of pioglitazone in depression associated with obesity.

Despite of the enormous research, therapeutic treatment for depression has always been a serious issue. Even though depression and obesity are individual abnormal health conditions, each act as a triggering factor for the other. Obese individuals are twice prone to develop depression than that of non-obese persons. The exact mechanism how obesity increases the risk for depression still remains an area of interest for research in neuropsychopharmacology. Depression and obesity share some common pathological pathways such as hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of oxidant/antioxidant system balance, higher level of inflammatory cytokines, leptin resistance, altered plasma glucose, insulin resistance, reduced neuronal brain derived neurotrophic factor (BDNF) and decreased serotonergic neurotransmission in various regions of brain. The antidepressant-like effect of 5-HT3 receptor antagonists through allosteric modulation of serotonergic pathways is well evident from several research investigations belonging to our and some in other laboratories. Furthermore, serotonin regulates diet intake, leptin, corticosterone, inflammatory mechanisms, altered plasma glucose, insulin resistance and BDNF concentration in brain. The present review deals with various biological mechanisms involved in depression co-morbid with obesity and 5-HT3 receptor antagonists by modulation of serotonergic system as a therapeutic target for such co-morbid disorder.

Depression is a chronic and debilitating mental disorder that often remains undertreated. It could be due to unclear understanding of pathophysiology and/or inconsistent efficacy of current pharmacotherapy. Since the discovery of the first effective medications in the late 1950s, a variety of agents have been developed, which are mainly based on correction of monoamine deficit. However, over time, many different strategies have been determined in an effort to improve the efficacy and reduce the untoward effects of the therapeutic intervention. This chapter compiles the relative efficacy and plausible mechanism of antidepressant activity of most current therapeutic approaches targeting a wide range of molecular and cellular pathways, implicated in the pathogenesis of depression. Emerging knowledge of key pathogenic mechanisms, such as the impairment of non-monoaminergic neurotransmission, in addition to monoaminergic neurotransmission, hypothalamic-pituitary-adrenal axis hyperactivity, alteration in neurogenesis signaling pathways, enhanced brain oxidative stress, and inflammatory activity, has led to a host of new molecular drug targets. Several of these have been validated through the preliminary use of lead compounds and therapeutic agents in animals and humans.

In our earlier study we reported the antidepressant activity of ondansetron in obese mice. The present study investigates the effect of ondansetron on depression and anxiety associated with obesity in experimental mice with biochemical evidences. Male Swiss albino mice were fed with high fat diet (HFD) for 14 weeks to induce obesity. Then the subsequent treatment with ondansetron (0.5 and 1 mg/kg, p.o.), classical antidepressant escitalopram (ESC) (10 mg/kg, p.o.) and vehicle (distilled water 10 ml/kg, p.o.) was given once daily for 28 days. Behavioral assay for depression including sucrose preference test, forced swim test (FST) and anxiety such as light dark test (LDT) and hole board test (HBT) were performed in obese mice. Furthermore, in biochemical estimations oral glucose tolerance test (OGTT), plasma leptin, insulin, corticosterone, brain oxidative stress marker malonaldehyde (MDA), antioxidant reduced glutathione (GSH) and serotonin assays were performed. Results indicated that HFD fed obese mice showed severe depressive and anxiety-like behaviors. Chronic treatment with ondansetron inhibited the co-morbid depression and anxiety in obese mice by increasing sucrose consumption in sucrose preference test and reducing the immobility time in FST, increasing time and transitions of light chamber in LDT, improving head dip and crossing scores in HBT compared to HFD control mice. Ondansetron in obese mice inhibited glucose sensitivity in OGTT, improved plasma leptin and insulin sensitivity, reversed hypothalamic pituitary adrenal (HPA) axis hyperactivity by reducing the corticosterone concentration, restored brain pro-oxidant/anti-oxidant balance by inhibiting MDA and elevating GSH concentrations and facilitated serotonergic neurotransmission. In conclusion, ondansetron reversed the co-morbid depression and anxiety associated with obesity in experimental mice by attenuating the behavioral and biochemical abnormalities.

Background: Malaria, an infectious disease transmitted by mosquitoes, has affected the world since the beginning of recorded human history and it remains an ensconced global health challenge even today. Among the various proteases, expressed in the life cycle of parasite, cysteine protease falcipain-2 plays a pivotal role in parasite food assimilation and inhibition of this protease cause deleterious effects on the growth of parasite. Methods: Employing a ligand-based approach, 1-(4-(substituted)piperazin-1-yl)-2-(phenylamino)ethanone derivatives were designed and synthesized from the starting material piperazine in a sequence of reactions. Structural assignments are based on spectral data ( 1 H NMR, mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Furthermore, molecular docking studies were performed using Glide 5.9 software to incur a precise picture of the active ligand at the atomic level which will be helpful in the discovery of new antimalarial drugs. Results: Among the screening results of seventeen novel entities, three compounds (6h, 6n and 6o) have showed good inhibitory activity and eleven compounds were showed weak to moderate inhibitor activity. Docking studies for these active analogues revealed that the amino acids Trp 206, Ile 85, Leu 84, Val 152 most commonly involved in hydrophobic interactions and Asn 173, Cys 42, Gln 36, amino acids involved in hydrogen bonding. Conclusion: The preliminary structure-activity relationships indicated that compound 6h, is the most potent compound from this series, and it can be used as a potential lead compound in the designing of new candidates to optimize the inhibitory potencies of this class of compounds, and potentially with potent antimalarial activity. Key words: Antimalarial, Falcipain-2, Ligand-based drug design, Plasmodium falciparum .

Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure-activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels.

Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity. Mice were fed with high fat diet (HFD) for 14 weeks, further subjected for treatment with QCM-4 (1 and 2 mg/kg p.o.) and standard antidepressant escitalopram (ESC) (10 mg/kg p.o.) for 28 days. Behavioral assays for depression such as sucrose preference test (SPT), forced swim test (FST) and for anxiety such as light and dark test (LDT) and hole board test (HBT) were performed in obese mice. Biochemical assessments including plasma leptin and corticosterone concentration followed by brain oxidative stress parameters malonaldehyde (MDA) and reduced glutathione (GSH) were performed. Results confirmed that QCM-4 exhibits antidepressive effect by increasing the sucrose consumption in SPT, reducing immobility time in FST and anxiolytic effect by increasing transitions and time in light chamber in LDT, increasing head dip and crossing score in HBT. Furthermore, QCM-4 attenuated the hypothalamic–pituitary–adrenal (HPA) axis hyperactivity by reducing the plasma corticosterone, reversing altered plasma leptin, restoring the imbalance of brain MDA and GSH concentration. In conclusion, QCM-4 showed antidepressive and anxiolytic effect by reversing the behavioral alterations that were supported by biochemical estimations in obese mice.

Background Chronic unpredictable stressors can produce a situation similar to human depression and such animal models can be used for the preclinical evaluation of antidepressants. The 5-HT 3 receptor antagonists modulate serotonergic pathways and show antidepressant-like effect in various animal models of depression. Methods In this study, a novel and potential 5-HT 3 receptor antagonist N -n-propyl-3-ethoxyquinoxaline-2-carboxamide ( 6n ) with good Log P (2.52) value and p A 2 (7.6) values, synthesized in our laboratory was explore to study the effects on CUMS-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour. Results CUMS caused depression-like behaviour in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test (FST) while there was no significant effect on spontaneous locomotor activity (SLA) observed. In addition it was found that lipid peroxide and nitrite levels were significantly increased, whereas glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in brain tissue of CUMS-treated mice. Compound 6n (1 and 2 mg/kg, po , 21 days) and fluoxetine treatment (20 mg/kg, po , 21 days) significantly altered the CUMS-induced behavioural (increased immobility period, reduced sucrose preference) and biochemical (increased lipid peroxidation, increased brain nitrite; decreased GSH, SOD and CAT levels) parameters while there was no significant effect of observed on SLA. Conclusion Compound 6n produced antidepressant-like effects in behavioural despair paradigm in chronically stressed mice by restoring antioxidant enzyme activity up to significant level.

The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure-activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity. Compound 33 exhibited potent antiparasitic activity (EC₅₀ 9.0±0.2μM), a 9-fold improvement over the antiparasitic activity of the hit molecule 6. Treatment of blood stage P. falciparum cultures with compound 33 caused morphological and developmental abnormalities in the parasites; further, compound 33 treatment hindered apicoplast development indicating the targeting of apicoplast.

BACKGROUND 5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models. METHODS LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined. RESULTS The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain. CONCLUSIONS Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.

Background Several preclinical studies have shown that serotonergic 5-HT3 receptor antagonists play an important role in the management of neuropsychiatric disorders, such as depression and anxiety. In the present study the compound "6n" (N-n-propyl-3-ethoxyquinoxaline-2-carboxamide), a novel 5-HT3 receptor antagonist with an optimal log P (2.52) and pA2 (7.6) value was screened for its neuro-pharmacological potential in chronic rodent models of depression and anxiety named traumatic brain injury (TBI). Methods In this model, a 1 cm midline scalp incision was made, and the muscles were retracted to expose the skull. A stainless steel disc (10 mm in diameter and 3 mm in depth) was placed centrally between the lambda and bregma regions. The injury was induced using the impact acceleration model of TBI. Specifically, a 400 g metal weight was dropped from a height of 1 m guided by a straight pipe, onto the metal disc placed over the rat's skull. Results The behavioral anomalies of the TBI rats were attenuated by the chronic treatment of compound 6n (1 and 2 mg/kg, p.o.; 14 days) as observed by the modified open field test (ambulation, rearing, and fecal pellet), sucrose consumption test (% sucrose consumption), elevated plus maze [% open arm entries [OAE] and % time spent in open arm (TSOA)], and marble burying test (numbers). In addition, 6n also increased the levels of neurotransmitters (norepinephrine and serotonin) and brain derived neurotrophic factor (BDNF) in TBI rats. Conclusions The result suggests that compound 6n exhibited antidepressant- and anxiolytic-like effects in rodent models of depression and anxiety.

INTRODUCTION: Obesity is an important risk factor for depression as more than half of the obese population is susceptible for depression at double rate. Our earlier studies reported the antidepressant potential of 5-HT3receptor antagonist, ondansetron (OND) in depression associated obesity using behavioral tasks. The present research work is aimed to evaluate the effect of OND on depression associated with obesity with special emphasis on biochemical and molecular mechanisms such as hippocampal brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP), 5-hydroxytryptamine (5-HT), hippocampal histological examination and immunohistochemical expression of p53 proteins. MATERIALS AND METHODS: Mice were fed with high-fat diet (HFD) for 14 weeks, followed by treatment schedule for 28 days with vehicle/OND (0.5 and 1 mg/kg, p.o.)/reference antidepressant escitalopram (10 mg/kg, p.o.). Subsequently, animals were screened in the behavioral tests of depression such as forced swim test (FST) and sucrose preference test (SPT), biochemical estimations including hippocampal cAMP, BDNF and 5-HT, and molecular assays mainly histology and p53 expression of dentate gyrus (DG). RESULTS: HFD-fed mice showed increased immobility time in FST, reduced sucrose consumption in SPT, decreased level of signal transduction factor cAMP, neuronal growth factor BDNF and neurotransmitter 5-HT in the hippocampus, and raised and p53 expression neuronal damage in the DG region of mice fed with HFD in comparison to the mice fed with normal pellet diet. Chronic treatment with OND (0.5 and 1 mg/kg, p.o.) significantly inhibited the behavioral, biochemical and molecular modifications in HFD-fed mice. CONCLUSION: In the preliminary study, OND attenuated depression associated with obesity in mice fed with HFD using various assays procedures, at least in part by the modulation of serotonergic transmission.

Aim: Depression and anxiety are among the most common and prevalent forms of mental disorder. The 5-hydroxytryptamine3 (5-HT 3 ) receptor antagonists modulate serotonergic pathways and show antidepressant- and anxiolytic-like effect in various animal models of depression. The present study was designed to investigate the antidepressant and anxiolytic potential of 2-[4-(3-chlorophenyl) piperazin-1-yl]- 1,8-naphthyridine-3-carboxylic acid (7e), a novel 5-HT 3 receptor antagonist in rodent behavioral models of depression and anxiety. Materials and Methods: The compound 7e was tested using different behavioral models for depression and anxiety such as forced swim test (FST), tail suspension test (TST), mechanistic models such as 5-hydroxytryptophan (5-HTP)-induced head twitch, elevated plus maze (EPM), hole-board (HB) test, open field test (OFT), and light and dark (L and D) aversion test. Results: The compound 7e (1 and 2 mg/kg, intraperitoneally [i.p.]) exhibits antidepressant-like effect in FST. In addition, compound 7e (0.5, 1 and 2 mg/kg, i.p.) exhibits antidepressant-like effect in TST after acute treatment without any significant effect on base line spontaneous locomotor activity. Moreover, compound 7e (2 mg/kg, i.p.) potentiated the 5-HTP-induced head twitch responses in mice. In interaction studies, compound 7e (0.5 mg/kg, i.p.) potentiated the antidepressant effect of bupropion. Furthermore, compound 7e also exhibited anxiolytic-like effect in EPM, HB test, OFT, and L and D aversion test. Conclusion: These preliminary studies reveal that compound 7e exhibits antidepressant- and anxiolytic-like effect in behavioral rodent models of depression and anxiety.