Ketamine, an NMDA receptor antagonist has been shown to induce aberrant behaviour phenotypes in rodents, some of which are known to simulate the behaviour abnormalities observed in patients suffering ...from schizophrenia. Thus, developing ketamine-induced animal models became an important tool of choice to study the mechanistic details of some critical symptoms associated with schizophrenia. In this study, our goal was to characterize and correlate the ketamine-induced changes in the behavioural phenotypes to the changes in neurochemical and molecular profile(s) in the brain tissues implicated in the pathophysiology of schizophrenia. We studied the effects of ketamine in mice using ‘acute’ and ‘chronic’ treatment regimens along with the ‘drug withdrawal’ effects on their biochemical and molecular parameters in the pre-frontal cortex, hippocampus, and striatum. Our results demonstrated that the acute and chronic ketamine administration, differentially and site specifically, modulated the levels of acetylcholine, dopamine, serotonin and noradrenaline. In addition, the chronic ketamine doses dramatically suppressed the levels of glycine among some of the amino acids examined and induced alternations in gene expression of the key neurotransmitter receptor systems, including some members of the dopamine and the serotonin receptor families. The acute and chronic ketamine treatment induced “signature” neurochemical and gene-expression patterns that are implicated in the pathophysiology of schizophrenia. Our analyses tend to support the “chronic ketamine” mice model for experimental psychosis as a tool for deeper investigation of the mechanistic paradigm associated with the schizophrenia spectrum disorder and for screening next-generation antipsychotic drugs.
► Characterization of neurochemical abnormalities induced by ketamine. ► Evaluation of the construct validity of the ketamine model of experimental psychosis. ► Abnormalities in neurotransmitter, amino acids and enzyme activity were studied. ► Chronic ketamine model possesses better construct validity than the acute model.
A series of novel 3-phenylcoumarin derivatives have been synthesized and evaluated for their in vivo antidepressant activities. The most active compound
6 was selected as lead compound for further ...antidepressant research.
A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (
6,
7 and
13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5
mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.
► We employed Caenorhabditis elegans strain expressing GFP in dopaminergic neurons for this study. ► Calorie restriction prevents dopaminergic cell death in 6-OHDA treated C. elegans. ► Sir-2.1 is ...required for the protective effect of calorie restriction on cell death.
The phenomenon of aging is known to modulate many disease conditions including neurodegenerative ailments like Parkinson’s disease (PD) which is characterized by selective loss of dopaminergic neurons. Recent studies have reported on such effects, as calorie restriction, in modulating aging in living systems. We reason that PD, being an age-associated neurodegenerative disease might be modulated by interventions like calorie restriction. In the present study we employed the transgenic Caenorhabditis elegans model (Pdat-1::GFP) expressing green fluorescence protein (GFP) specifically in eight dopaminergic (DA) neurons. Selective degeneration of dopaminergic neurons was induced by treatment of worms with 6-hydroxy dopamine (6-OHDA), a selective catecholaminergic neurotoxin, followed by studies on effect of calorie restriction on the neurodegeneration. Employing confocal microscopy of the dopaminergic neurons and HPLC analysis of dopamine levels in the nematodes, we found that calorie restriction has a preventive effect on dopaminergic neurodegeneration in the worm model. We further studied the role of sirtuin, sir-2.1, in modulating such an effect. Studies employing RNAi induced gene silencing of nematode sir-2.1, revealed that presence of Sir-2.1 is necessary for achieving the protective effect of calorie restriction on dopaminergic neurodegeneration.
Our studies provide evidence that calorie restriction affords, an sir-2.1 mediated, protection against the dopaminergic neurodegeneration, that might have implications for neurodegenerative Parkinson’s disease.
Stress is a global menace fortified by the advancement of industrialization. Failure of stress management is due to lack of proper evaluation of anti-stress products. We explored the anti-stress ...potential of the Ginkgo biloba (G. biloba, 30 mg/kg, p.o.) and compared it with that of Panax ginseng (P. ginseng, 100 mg/kg, p.o.) against acute stress (AS) and chronic stress (CS) models in rats. Immediately after AS and CS, the rats were sacrificed, and adrenal glands and stomach were dissected out for weight determination and scoring of the ulcer index (UI), respectively, as well as changes in biochemical parameters like plasma glucose (GL), triglycerides (TG), cholesterol (CL), creatine kinase (CK), and serum corticosterone (CORT) were also estimated. AS significantly increased UI, adrenal gland weight (AGW), GL, CK activity, and CORT, whereas G. biloba significantly reduced them. P. ginseng significantly reverted GL and CK activity. In CS, a significant increase was found in the UI, AGW, CK activity, and CORT with a decrease in the level of CL and TG. G. biloba did not produce any significant effect on CS-induced alterations. P. ginseng reduced the UI, AGW, plasma GL, TG, CK activity, and CORT level significantly. From the above study, G. biloba is more effective in AS, whereas for CS, P. ginseng will be a better option. Hence these extracts possess significant anti-stress properties and can be used for the treatment of stress-induced disorders.
▸ Tyrosine hydroxylase and glucocorticoid receptor were analyzed in stress models. ▸ A68930 normalized the stress-induced alterations in distinct brain regions. ▸ A68930 inhibits oxidative stress by ...modulation of antioxidant system. ▸ A68930 may be of therapeutic use for the treatment of dopamine-related disorders.
The neurorescuing effect of A68930 (a potent selective D1 agonist) and its role on the regulation of hypothalamus–pituitary–adrenal (HPA)-axis have been investigated. Acute (AS) and chronic unpredictable (CUS) stress models were used to evaluate the effect of A68930 on HPA-axis regulation in relation to the change in the fiber density and number of immunoreactive (ir) neurons of tyrosine hydroxylase (TH) and glucocorticoid receptor (GR) in the dopamine (DA) and GR rich brain regions in rats. CUS caused a significant decrease in the number of TH ir neurons in the striatum, medial forebrain bundle, ventral tegmental area and substansia nigra and GR in the cortex, striatum and hippocampus as compared to the non-stress controls (NS). Administration of A68930 (0.25mg/kg i.p.) significantly normalized these CUS-induced alterations. We also examined the role of A68930 on stress-induced brain oxidative status. AS enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the cortex and striatum, while CUS reduced the activities of SOD and catalase (CAT) in the cortex, striatum and hippocampus, when compared with NS. Increased GSH-Px activity, with reduced glutathione and increased lipid peroxidation was observed in both AS and CUS in selected brain regions as compared to NS. Administration of A68930 normalized the antioxidant enzyme activities, replenished GSH and decreased the extent of lipid peroxidation. In conclusion, present findings suggest that the stress-induced immunoreactivity of TH and GR in distinct brain regions are modulated by A68930 leading to the normalization of HPA-axis response. Ours results show the therapeutic importance of DA D1 agonist in stress-induced dopaminergic-related neurological disorders. A68930 also influenced the brain antioxidant machinery probably through the restoration of stress-induced changes in the dopaminergic system and its crosstalk with GR.
We aimed to evaluate the response of dopaminergic system in acute stress (AS) and chronic unpredictable stress (CUS) by measuring dopamine (DA) levels, its receptor densities in the frontal cortex, ...striatum, hippocampus, amygdala and orbito-frontal cortex regions of rat brain, and investigated the corresponding behavioral locomotor changes. Involvement of D
1
receptor was also examined during AS and CUS using A 68930, a D
1
selective agonist. Rats were exposed to AS (single immobilization for 150 min) and CUS (two different stressors for 7 days). AS significantly decreased the DA levels in the striatum and hippocampus, and A 68930 pretreatment significantly reverted these changes. However, in the frontal cortex significantly increased DA levels were remain unchanged following A 68930. CUS led to a decrease of DA levels in the frontal cortex, striatum and hippocampus, which were normalized by A 68930. Saturation radioligand binding assays revealed a significant decrease in the number of D
1
-like receptors in the frontal cortex during CUS, which were further decreased by A 68930 pretreatment. However, in the striatum and hippocampus, A 68930 pretreatment reduced the CUS induced increase in the number of D
1
-like receptors. No significant changes were observed in the amygdala and orbito-frontal cortex during AS and CUS, while D
2
-like receptors were unchanged in all the brain regions studied. Locomotor activity was significantly decreased in both the stress models, A 68930 pretreatment significantly increased stereotypic counts and horizontal activity. Thus, present investigation provide insights into the differential regional response of dopaminergic system during AS and CUS. Further, neurochemical and behavioral effects of D
1
agonist pretreatment suggest specific modulatory role of D
1
receptor under such stressful episodes.
Ocimum sanctum (OS) is known to possess various therapeutic properties. We evaluated its anti-ulcerogenic activity in cold restraint (CRU), aspirin (ASP), alcohol (AL), pyloric ligation (PL) induced ...gastric ulcer models in Sprague–Dawley rats, histamine-induced duodenal (HST) ulcer in guinea pigs, and ulcer-healing activity, in acetic acid-induced (AC) chronic ulcer model. We found that OS
, decreased the incidence of ulcers and also enhanced the healing of ulcers. OS at a dose of 100
mg/kg was found to be effective in CRU (65.07%), ASP (63.49%), AL (53.87%), PL (62.06%), and HST (61.76%) induced ulcer models and significantly reduced free, total acidity and peptic activity by 72.58, 58.63, 57.6%, respectively, and increased mucin secretion by 34.61%. Additionally, OS completely healed the ulcers within 20 days of treatment in AC. We observed that anti-ulcer effect of OS may be due to its cytoprotective effect rather than antisecretory activity. Conclusively, OS was found to possess potent anti-ulcerogenic as well as ulcer-healing properties and could act as a potent therapeutic agent against peptic ulcer disease.
Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the ...effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE
2 content and proton pump activity. The dopamine D
1 receptor agonist (A 68930) and antagonist (SCH 23390), and D
2 receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150
min) and chronic unpredictable stress (two different types of stressors for 7
days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60
mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25
mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1–0.5
mg/kg) and quinpirole (0.1–0.5
mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under
in-vitro condition. A 68930 (10–50
μg/ml) inhibited the gastric H
+ K
+-ATPase activity comparable to positive control omeprazole, while sulpiride (10–50
μg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D
1 agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions.
As stress is linked to many diseases, research on an effective antistress agent (adaptogen) from plants has gained importance. We report the investigations on the adaptogenic property of a ...standardized extract of
Bacopa monniera against acute (AS) and chronic stress (CS) models in rats.
Panax root powder (
Panax quinquefolium) was taken as a standard. Male SD rats, weighing 180–200 g, exposed to immobilization stress for 150 min once only for AS and for seven consecutive days in CS, were fed with
B. monniera or
Panax root powder daily for 3 days in AS and for 7 days in CS, 45 min prior to each exposure of stress. Rats were sacrificed immediately after stress, the blood was collected, and the plasma was separated out for biochemical estimation. Adrenals, spleen, and thymus were dissected for organ weight and stomach for ulcer score. AS exposure significantly increased the ulcer index, adrenal gland weight, plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) but significantly decreased the spleen weight. Pretreatment with
B. monniera at 40 mg/kg po significantly reduced the AS-induced increase in the ulcer index, adrenal gland weight, plasma glucose, AST, and CK. A dose of 80 mg/kg po significantly reversed the AS-induced changes in adrenal gland weight, spleen weight, plasma glucose, ALT, and AST.
Panax root powder, 100 mg/kg po, significantly reversed the AS-induced changes in spleen weight, plasma ALT, AST, and CK. CS exposure resulted in a significant increase in the ulcer index, adrenal gland weight, plasma AST, and CK with a significant decrease in the thymus and spleen weight, plasma triglyceride, and cholesterol. Pretreatment with low dose of
B. monniera extract at 40 mg/kg significantly reversed changes in ulcer index and plasma AST only, whereas the pretreatment with higher dose significantly reversed CS-induced changes in ulcer index, adrenal gland weight, CK, and AST.
Panax root powder significantly reversed CS-induced increase in ulcer index, adrenal gland weight, CK, and AST. On the basis of our result, it is concluded that the standardized extract of
B. monniera possesses a potent adaptogenic activity.
Bioactivity-guided purification of n-BuOH soluble fraction from the ethanol extract of Evolvulus alsinoides resulted in the isolation of two new compounds, 2,3,4-trihydroxy-3-methylbutyl ...3-3-hydroxy-4-(2,3,4-trihydroxy-2-methylbutoxy)-phenyl-2-propenoate (1) and 1,3-di-O-caffeoyl quinic acid methyl ester (2) along with six known compounds, caffeic acid (3), 6-methoxy-7-O-β-glucopyranoside coumarin (4), 2-C-methyl erythritol (5), kaempferol-7-O-β-glucopyranoside (6), kaempferol-3-O-β-glucopyranoside (7) and quecetine-3-O-β-glucopyranoside (8). The structure of new compounds 1 and 2 were elucidated by spectroscopic analysis, while known compounds were confirmed by direct comparison of their NMR data with those reported in literature. This is the first report of the presence of phenolic constituents in Evolvulus alsinoides. The isolated compounds 1—5 and 8 were screened for anti-stress activity in acute stress induced biochemical changes in adult male Sprague–Dawley rats. Stress exposure has resulted in significant increase of plasma glucose, adrenal gland weight, plasma creatine kinase (CK), and corticosterone levels. Compound 1 displayed most promising antistress effect by normalizing hyperglycemia, plasma corticosterone, CK and adrenal hypertrophy, while compounds 2 and 3 were also effective in normalizing most of these stress parameters, however compounds 4, 5 and 8 were ineffective in normalizing these parameters.
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