Converged avenues: depression and Alzheimer's disease- shared pathophysiology and novel therapeutics.

Depression, a highly prevalent disorder affecting over 280 million people worldwide, is comorbid with many neurological disorders, particularly Alzheimer's disease (AD). Depression and AD share overlapping pathophysiology, and the search for accountable biological substrates made it an essential and intriguing field of research. The paper outlines the neurobiological pathways coinciding with depression and AD, including neurotrophin signalling, the hypothalamic-pituitary-adrenal axis (HPA), cellular apoptosis, neuroinflammation, and other aetiological factors.

Ondansetron ameliorates depression associated with obesity in high-fat diet fed experimental mice: An investigation-based on the behavioral, biochemical, and molecular approach.

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-HT receptor 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.

A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents.

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.

Antidepressant & anxiolytic activities of N-(pyridin-3-yl) quinoxalin-2-carboxamide: A novel serotonin type 3 receptor antagonist in behavioural animal models.

Background & Objectives: Alteration in the serotonin leads to the psychological illness, such as depression, anxiety, schizophrenia, eating disorders, obsessive-compulsive disorder, panic disorders and migraines. The objective of the current study was to investigate the antidepressant and anxiolytic activities of N-(pyridin-3-yl) quinoxalin-2-carboxamide (QCF-21), a novel 5-HT3receptor antagonist in preclinical models of depression and anxiety.

Methods: Antidepressant activity was evaluated in preliminary tests such as forced swim and tail suspension tests (FST & TST).

Molecular modifications by regulating cAMP signaling and oxidant-antioxidant defence mechanisms, produce antidepressant-like effect: A possible mechanism of etazolate aftermaths of impact accelerated traumatic brain injury in rat model.

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.

Pioglitazone, a PPARγ agonist rescues depression associated with obesity using chronic unpredictable mild stress model in experimental mice.

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.

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice.

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.

Neuropharmacological and neurochemical evaluation of N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n): a novel serotonergic 5-HT3 receptor antagonist for co-morbid antidepressant- and anxiolytic-like potential using traumatic brain injury model in rats.

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.

5HT3 receptors: Target for new antidepressant drugs.

5HT3 receptors (5HT3Rs) have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3Rs produces antidepressant-like effects. However, the exact role of 5HT3Rs and the mode of antidepressant action of 5HT3R antagonists still remain a mystery.

A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes.

Mechanisms linking depression co-morbid with obesity: An approach for serotonergic type 3 receptor antagonist as novel therapeutic intervention.

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.

Ondansetron attenuates co-morbid depression and anxiety associated with obesity by inhibiting the biochemical alterations and improving serotonergic neurotransmission.

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 14weeks to induce obesity.

Pharmacological evaluation of novel 5-HT3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery.

Objective: In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery.

Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents.

Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3', with various targeted substitutions to understand the structure-activity relationships.

Diabetes-associated depression: the serotonergic system as a novel multifunctional target.

Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of the existing conventional drugs with poor outcome may be, in part, due to uncertainty of the mechanism involved that clearly explains the existing comorbidity. The main purpose of this review was to address the sophisticated mechanisms of this comorbidity with a view of developing potential novel targets with higher efficacy and specificity.

Type 4 phosphodiesterase enzyme inhibitor, rolipram rescues behavioral deficits in olfactory bulbectomy models of depression: Involvement of hypothalamic-pituitary-adrenal axis, cAMP signaling aspects and antioxidant defense system.

Olfactory bulbectomy (OBX) model has been proposed as a well documented model of depression. Accumulated evidences suggest that cAMP selective PDE4 enzyme plays an important role in the pathophysiology of depression disorder. Moreover, PDE4 inhibitors have shown antidepressant-like effect in behavioral despair models.

Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice.

Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents.

Piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides: novel 5-HT3 receptor antagonists with antidepressant-like activity.

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.

QCM-4, a 5-HT₃ receptor antagonist ameliorates plasma HPA axis hyperactivity, leptin resistance and brain oxidative stress in depression and anxiety-like behavior in obese mice.

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.

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression.

Aim: To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression.

Methods: 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.

Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: possible implication of serotonergic system.

Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes.

Antidepressant-like effect of a novel 5-HT3 receptor antagonist N-(benzo[d] thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide 6k using rodents behavioral battery tests.

Objective: To investigate the antidepressant-like effect of N-(benzo[d] thiazol-2-yl)-3- ethoxyquinoxalin-2-carboxamide 6k, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist using rodents behavioral battery tests.

Materials And Methods: 6k screening was performed with behavioral assays for depression-like forced swim test (FST) at several single doses (0.25-4 mg/kg, intraperitoneal injection (i.

Anxiolytic-like effects of alverine citrate in experimental mouse models of anxiety.

Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Despite a consistent increase in anxiolytics, the prevalence of anxiety is static; this necessitates the development of new compounds with potential activity and minimum unwanted effects. A serotonergic (5HT) system plays an important role in pathogenesis of anxiety and predominantly involves 5HT1A receptor action in mediating anxiety-like behavior; the antagonism of 5HT1A receptor has demonstrated to produce anxiolytic-like effects.

Neuropharmacological effect of novel 5-HT3 receptor antagonist, N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) on chronic unpredictable mild stress-induced molecular and cellular response: Behavioural and biochemical evidences.

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-HT3 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-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n) with good Log P (2.

Etazolate, a phosphodiesterase-4 enzyme inhibitor produces antidepressant-like effects by blocking the behavioral, biochemical, neurobiological deficits and histological abnormalities in hippocampus region caused by olfactory bulbectomy.

Rationale: Olfactory bulbectomy (OBX) is a widely used model for antidepressant screening and known to induce neurodegeneration in several brain areas. Our earlier studies demonstrated that etazolate produced antidepressant-like effects in behavioral despair models of depression; however, the potential role of etazolate on behavior and morphological changes in the hippocampus region along with its underlying mechanism(s) following OBX has not been adequately addressed.

Objectives: We evaluated if etazolate could protect against OBX-induced depression-like behavioral deficits and neurodegeneration.