Chronic unpredictable stress negatively regulates hippocampal neurogenesis and promote anxious depression-like behavior via upregulating apoptosis and inflammatory signals in adult rats.

Psychological and physical stress play a pivotal role in etiology of anxiety and depression. Chronic psychological and physical stress modify various physiological phenomena, as a consequence of which oxidative stress, decreased neurotransmitter level, elevated corticosterone level and altered NSC homeostasis is observed. However, the precise mechanism by which chronic stress induce anxious depression and modify internal milieu is still unknown. Herein, we show that exposure to CUS increase oxidative stress, microgliosis, astrogliosis while it reduces hippocampal NSC proliferation, neuronal differentiation and maturation in adult rats. CUS exposure in rats reduce dopamine and serotonin level in cortex and hippocampus, which result in increased anxiety and depression-like phenotypes. We also found elevated level of NF-κB and TNF-α while decreased anti-inflammatory cytokine IL-10 level, that led to increased expression of Bax and cleaved Caspase-3 whereas down regulation of antiapoptotic protein Bcl2. Additionally, CUS altered adult hippocampal neurogenesis, increased gliosis and neuronal apoptosis in cerebral cortex and hippocampus which might be associated with reduced AKT and increased ERK signaling, as seen in the rat brain tissue. Taken together, these results indicate that CUS induce oxidative stress and neuroinflammation which directly affects NSC dynamics, monoamines levels and behavioral functions in adult rats.

Oral acetate supplementation attenuates N-methyl D-aspartate receptor hypofunction-induced behavioral phenotypes accompanied by restoration of acetyl-histone homeostasis.

RATIONALE: Aberrations in cellular acetate-utilization processes leading to global histone hypoacetylation have been implicated in the etiology of neuropsychiatric disorders like schizophrenia. OBJECTIVES: Here, we investigated the role of acetate supplementation in the form of glyceryl triacetate (GTA) for the ability to restore the N-methyl D-aspartate (NMDA) receptor-induced histone hypoacetylation and to ameliorate associated behavioral phenotypes in mice. RESULTS: Taking cues from the studies in SH-SY5Y cells, we monitored acetylation status of specific lysine residues of histones H3 and H4 (H3K9 and H4K8) to determine the impact of oral GTA supplementation in vivo. Mice treated chronically with MK-801 (10 days; 0.15 mg/kg daily) induced hypoacetylation of H3K9 and H4K8 in the hippocampus. Daily oral supplementation of GTA (2.9 g/kg) was able to prevent this MK801-induced hypoacetylation significantly. Though MK-801-stimulated decreases in acetyl-H3K9 and acetyl-H4K8 were found to be associated with ERK1/2 activation, GTA seemed to act independent of this pathway. Simultaneously, GTA administration was able to attenuate the chronic MK-801-induced cognitive behavior phenotypes in elevated plus maze and novel object recognition tests. Not only MK-801, GTA also demonstrated protective effects against behavioral phenotypes generated by another NMDA receptor antagonist, ketamine. Acute (single injection) ketamine-mediated hyperactivity phenotype and chronic (10 days treatment) ketamine-induced phenotype of exaggerated immobility in forced swim test were ameliorated by GTA. CONCLUSION: The signature behavioral phenotypes induced by acute and chronic regimen of NMDA receptor antagonists seemed to be attenuated by GTA. This study thus provides a therapeutic paradigm of using dietary acetate supplement in psychiatric disorders.

Administration of N-acetylserotonin and melatonin alleviate chronic ketamine-induced behavioural phenotype accompanying BDNF-independent and dependent converging cytoprotective mechanisms in the hippocampus.

Though growing evidence implicates both melatonin (MLT) and its immediate precursor N-acetylserotonin (NAS) in the regulation of hippocampal neurogenesis, their comparative mechanistic relationship with core behavioural correlates of psychiatric disorders is largely unknown. To address this issue, we investigated the ability of these indoleamines to mitigate the behavioral phenotypes associated with NMDA-receptor (NMDAR) hypofunction in mice. We demonstrated that exogenous MLT and NAS treatments attenuated the NMDAR antagonist (ketamine) induced immobility in the forced swim test (FST) but not the classical striatum-related hyperlocomotor activity phenotype. The MLT/NAS-mediated protection of the phenotype in FST could be correlated to the ability of these indoleamines to counteract the deleterious effects of chronic ketamine on pro-survival molecular events by restoring the activities in MEK-ERK and PI3K-AKT pathways in the hippocampus. MLT seems to modulate these pathways by promoting accumulation of the mature form of BDNF above the control (vehicle-treated) levels, perhaps via MLT receptor-dependent mechanisms and in the process overcoming the ketamine-induced down-regulation of BDNF. In contrast, NAS appears to partly restore the ketamine-induced decrease of BDNF to the control levels. In spite of this fundamental difference in modulating BDNF levels in the upstream events, both MLT and NAS seem to overlap in the TrkB-induced downstream pro-survival mechanisms in the hippocampus, providing protection against NMDAR-hypofunction related cellular events. Perhaps, this also signifies the physiological importance of robust MLT synthesizing machinery that converts serotonin to MLT, in ensuring positive impact on hippocampus-related symptoms in psychiatric disorders.

Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems.

CONTEXT: Schizophrenia is a chronic disabling psychiatric disorder affecting 1% of the population worldwide. Due to the adverse effects of available antipsychotic medications, recent investigations have focused on the search for well-tolerated, safe molecules from natural resources to control the severity and progression of schizophrenia. OBJECTIVE: To screen the standardized extract of Bacopa monniera Linn. (Scrophulariaceae) (BM) for its antipsychotic potential in the ketamine-induced psychosis model with mice. MATERIALS AND METHODS: Graded dose of BM (40, 80, and 120 mg/kg, p.o.) were given to the mice 1 h prior to ketamine administration and tested for positive symptoms and cognitive deficits. A chronic ketamine treatment regimen was used to study the effect of BM on negative symptoms such as immobility enhancement. Each mouse was used once for the behavioral studies. RESULTS: BM reduced ketamine-induced hyperactivity with an EC50 value of 76.60 mg/kg. The 80 mg/kg dose was used for all other behavior analysis. Pretreatment with BM at 80 mg/kg showed two-fold increases in transfer latency time (TLT) in passive avoidance task. Chronic BM pretreatment (80 mg/kg p.o. daily × 10 d) ameliorated the ketamine-induced enhanced immobility effect by 21% in the forced swim test. BM treatment reversed ketamine-induced increase in monoamine oxidase activity in both cortex and striatum and normalized the acetylcholinesterase activity and the glutamate levels in the hippocampus. DISCUSSION AND CONCLUSION: Overall our findings suggest that BM possesses antipsychotic properties which might be due to its modulatory action on dopamine, serotonin, and glutamate neurotransmission.

Cytoprotective and Anti-secretory Effects of Azadiradione Isolated from the Seeds of Azadirachta indica (neem) on Gastric Ulcers in Rat Models.

Azadirachta indica is well known medicinal plant mentioned in ancient herbal texts. It has been extensively used in Ayurvedic, Unani and Homoeopathic medicine and has become a luminary of modern medicine. As part of our drug discovery program we isolated azadiradione from the ethanolic extract of seeds of A. indica and evaluated for in-vivo antiulcer activity in cold restraint induced gastric ulcer model, aspirin induced gastric ulcer model, alcohol induced gastric ulcers model and pyloric ligation induced ulcer model. Azadiradione exhibited potent antiulcer activity through the inhibition of H+ K+-ATPase (proton pump) activity via its cytoprotective effect and also via its antisecretory effect. This combined effect has valuable potential in the future treatment of peptic ulceration.

Identification of quinoline-chalcone hybrids as potential antiulcer agents.

Antiulcer activity of novel quinoline-chalcone hybrids (13-37) was investigated. Among them, eight compounds (14, 16, 17, 23, 29, 31, 32 and 35) were found to be active in various ulcer models in Sprague-Dawley (SD) rats. To understand the mechanism of action of these hybrids, the effects of the compounds on antisecretory and cytoprotective activities were studied. All these active hybrids improved the depleted levels of mucin and consequently inhibited the formation of erosions in a pyloric ligated ulcer model. In addition, they also significantly increased the gastric PGE2 content in an aspirin induced ulcer model. The additional experiments including the in vitro metabolic stability and in vivo pharmacokinetics led to the identification of compound 17 as an orally active and safe candidate that is worthy of further investigation to be developed as an antiulcer agent.

In vivo gastroprotective effect of xyloccensin-E and xyloccensin-I from Xylocarpus molluccensis in rats.

Anti-ulcer activities of xyloccensin-E and xyloccensin-I were investigated in various ulcer models in Sprague-Dawley rats. The effects and the mechanism of action of both compounds for anti-secretory and cytoprotective activities were also studied. Both these active molecules improved the depleted levels of mucin and consequently inhibited the formation of erosions in a pyloric ligated ulcer model. Furthermore, xyloccensin-E and xyloccensin-I inhibited H(+)K(+)-ATPase activity in vitro confirming their anti-secretory activity. In conclusion, xyloccensin-E and xyloccensin-I were found to possess anti-ulcerogenic activity which might be due to their anti-secretory activity and subsequent strengthening of the defensive mechanism.

A new gastroprotective effect of limonoid compounds xyloccensins x and y from xylocarpus molluccensis in rats.

Gastric ulcer is a very common gastrointestinal disorder affecting a large number of people worldwide. It arises due to an imbalance between aggressive (acid, pepsin and Helicobacter pylori infection) and protective (mucin secretion, prostaglandin, epidermal growth factors and bicarbonate) factors in the stomach. In this study, the gastroprotective activity has been investigated of the active constituents from Xylocarpus molluccensis. Antiulcer activity of xyloccensins X+Y was investigated and found to be active in various ulcer models in Sprague-Dawley (SD) rats. To understand the mechanism of action of active constituent of natural products, the effects of the compounds on antisecretory and cytoprotective activities were studied. Air dried fruits were extracted with ethanol and fractionated into four fractions. Xyloccensins X+Y were isolated from the active fraction and was tested against different ulcer models. Xyloccensins X+Y were found to possess anti-ulcerogenic activity. The antiulcer activity might be due to its anti-secretory activity and subsequent strengthening of the defensive mechanism. The present study has helped us in identifying a new lead in the form of xyloccensins that could be exploited in the treatment of gastric ulcer disease.

Anti-secretory and cyto-protective effects of peganine hydrochloride isolated from the seeds of Peganum harmala on gastric ulcers.

Gastroprotective mechanism of peganine hydrochloride isolated from Peganum harmala seeds was investigated. Peganine hydrochloride was evaluated against cold restraint (CRU), aspirin (AS), alcohol (AL) and pyloric ligation (PL) induced gastric ulcer models in rats. Potential anti-ulcer activity of peganine was observed against CRU (50.0%), AS (58.5%), AL (89.41%) and PL (62.50%) induced ulcer models. The reference drug omeprazole (10mg/kg, p.o.) showed 77.45% protection against CRU, 49.97% against AS and 69.42% against PL model. Sucralfate, another reference drug (500mg/kg, p.o.) showed 62.50% protection in AL induced ulcer model. Peganine significantly reduced free acidity (33.38%), total acidity (38.09%) and upregulated mucin secretion by 67.91%, respectively. Further, peagnine significantly inhibited H(+) K(+)-ATPase activity in vitro with IC50 of 73.47µg/ml as compared to the IC50 value of omeprazole (30.24µg/ml) confirming its anti-secretory activity.

Arbortristoside-A and 7-O-trans-cinnamoyl-6ß-hydroxyloganin isolated from Nyctanthes arbortristis possess anti-ulcerogenic and ulcer-healing properties.

Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery program on Indian medicinal plants, we isolated arbortristoside-A (AT) and 7-O-trans-cinnamoyl-6ß-hydroxyloganin (6-HL) from the seeds of N. arbortristis. AT and 6-HL exhibited anti ulcer activity in experimentally induced ulcer models including cold restraint stress (CRU), alcohol (AL), pylorus ligation-induced gastric ulcer (PL) models and they also showed ulcer healing effect in chronic acetic acid-induced ulcer model (AC).

Anxiolytic effects of Plumeria rubra var. acutifolia (Poiret) L. flower extracts in the elevated plus-maze model of anxiety in mice.

Interest in alternative medicine and plant-derived medications that affect the "mind" is growing rapidly since last two decades. The aim of the present study was to investigate the effects of ethanolic extract of flower of Plumeria rubra (PR) along with its fractions in the elevated plus-maze (EPM) model of anxiety. The P. rubra extract or its fractions was administered orally to male Swiss mice, at graded doses, 1h prior to behavioural assessment. The PR extract at the dose of 100mg/kg p.o., significantly increased the time spent in the open arms of the EPM. Further, the anxiolytic properties of hexane, chloroform and butanolic soluble and insoluble fractions at one-fifth of the original dose were also observed in the EPM task. Out of which butanol insoluble fraction showed significant anxiolytic activity comparable to standard anxiolytic drug, diazepam. Further, pretreatment with crude ethanolic extract and butane insoluble fraction showed no significant effects in the horizontal activity, total distance travelled and stereotypy count in the animal activity monitor and had no motor in-coordination side effects in the rotarod test in mice. These observations suggest that the flower extract of P. rubra and its insoluble butanolic fraction might possess significant anxiolytic potential to be pursued further for drug development process.

Anti-secretory and cyto-protective effects of chebulinic acid isolated from the fruits of Terminalia chebula on gastric ulcers.

In continuation of our drug discovery program on Indian medicinal plants, the gastro protective mechanism of chebulinic acid isolated from Terminalia chebula fruit was investigated. Chebulinic acid was evaluated against cold restraint (CRU), aspirin (AS), alcohol (AL) and pyloric ligation (PL) induced gastric ulcer models in rats. Potential anti-ulcer activity of chebulinic acid was observed against CRU (62.9%), AS (55.3%), AL (80.67%) and PL (66.63%) induced ulcer models. The reference drug omeprazole (10 mg/kg, p.o.) showed 77.73% protection against CRU, 58.30% against AS and 70.80% against PL model. Sucralfate, another reference drug (500 mg/kg, p.o.) showed 65.67% protection in AL induced ulcer model. Chebulinic acid significantly reduced free acidity (48.82%), total acidity (38.29%) and upregulated mucin secretion by 59.75% respectively. Further, chebulinic acid significantly inhibited H(+) K(+)-ATPase activity in vitro with IC50 of 65.01 µg/ml as compared to the IC50 value of omeprazole (30.24 µg/ml) confirming its anti-secretory activity.

Identification of novel amino acid derived CCK-2R antagonists as potential antiulcer agent: homology modeling, design, synthesis, and pharmacology.

The present study revisited the three-dimensional (3D) homology model of CCK-2R using human A(2a) adenosine receptor and the resolved NMR based structure of the third extracellular loop of the CCK-2R as templates. Further in order to identify novel antiulcer agents, rational designing have been performed utilizing the substructure of a well-known CCK-2R antagonist benzotript as a lead molecule and submitted to the combined docking and simulation studies. This led to the understanding of the essential structure requirement as well as variation of binding mode among conformational isomers of small molecule CCK-2R antagonists. In the next step, preparation of each configurational isomer of these molecules was carried out and submitted for their in vitro activity followed by in vivo screening into antiulcer rat model. The biological screening of these compounds has not only validated the developed homology model of CCK-2R but also led to the identification of highly potent CCK-2R antagonist 6a as an orally active and safe candidate molecule having better antiulcer properties than the well-known drug benzotript.

Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice.

The root decoction of Cnestis ferruginea (CF) Vahl DC (Connaraceae) is used in traditional African medicine in the management of psychiatric disorders. This study presents the antidepressant and anxiolytic effects of amentoflavone (CF-2) isolated from the root extract of C. ferruginea. The antidepressant effect was studied using the forced swimming (FST) and tail suspension tests (TST) while the hole-board, elevated plus maze (EPM) and light/dark tests were used to evaluate the anxiolytic effect. Acute treatment with CF extract and amentoflavone significantly (p<0.001) reduced the duration of immobility in FST and TST with peak effects observed at 100 and 50mg/kg respectively in comparison to control treated. Antidepressant effects of CF and amentoflavone were significantly higher (p<0.05) when compared to imipramine in FST but comparable to the fluoxetine treated group in TST. The pretreatment of mice with metergoline (4mg/kg, i.p., a 5-HT2 receptor antagonist), prazosin (62.5µg/kg, i.p., an α1-adrenoceptor antagonist), and yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist), but not sulpiride (50mg/kg, i.p., a dopamine D2 receptor antagonist), cyproheptadine (3mg/kg, i.p., a 5-HT2 receptor antagonist), atropine (1mg/kg, i.p., a muscarinic receptor antagonist) 15mins before the administration of amentoflavone (50mg/kg; p.o.) significantly prevented its antiimmobility effect in the FST. CF extract and CF-2 significantly (p<0.05) attenuated anxiety by increasing the number of head-dips in the hole-board test, the time spent on the open arms in the EPM, and the exploration of the light chamber in the light/dark test. Pretreatment with flumazenil (3mg/kg, i.p., ionotropic GABA receptor antagonist) 15min before oral administration of amentoflavone (25mg/kg) significantly reduced the time spent in the open arms in EPM. It is concluded from the results obtained that amentoflavone produces its antidepressant effect through interaction with 5-HT2 receptor and α1-, and α2-adrenoceptors while the anxiolytic effect involved the ionotropic GABA receptor.

Restraint stress-induced central monoaminergic & oxidative changes in rats & their prevention by novel Ocimum sanctum compounds.

BACKGROUND & OBJECTIVES: Ocimum sanctum (OS) is known to possess various therapeutic properties. We have earlier isolated and characterized three OS compounds; Ocimarin, Ocimumoside A and Ocimumoside B. However, their role in modulating stress-induced central changes is unexplored. Thus, the present study was aimed to investigate the effect of these OS compounds on restraint stress (RS)-induced changes in the monoaminergic and antioxidant systems in the frontal cortex, striatum and hippocampus of rats. METHODS: RS was produced by immobilizing (restraining) the Sprague Dawley rats for a period of 2.5 h inside cylindrical steel tubes. The monoamine levels and the in vivo antioxidant status in brain regions were evaluated by HPLC-EC and spectrophotometric assays, respectively. RESULTS: RS significantly increased the dopamine levels in the frontal cortex and decreased in the striatum and hippocampus, and accompanied with selective increase of dopamine metabolites compared to the NS control group. The serotonin and its metabolite levels were significantly increased, while noradrenaline levels were decreased by RS in the three brain regions studied. The activities of superoxide dismutase and glutathione peroxidase in the frontal cortex and striatum were significantly increased by RS with decreased glutathione levels and increased lipid peroxidation. Pre-treatment with Ocimumoside A and B (40 mg/kg po) for a period of 3 days prevented the RS-induced changes with an efficacy similar to that of standard anti-stress (Panax quinquefolium; 100 mg/kg po) and antioxidant (Melatonin; 20 mg/kg ip) drugs, while, Ocimarin failed to modulate these changes. OS compounds per se had no effect on these parameters. INTERPRETATION & CONCLUSIONS: The present findings showed the anti-stress potential of Ocimumoside A and B in relation to their simultaneous modulatory effects on the central monoaminergic and antioxidant systems implicating their therapeutic importance in stress-related disorders. Further studies are required to understand the mechanism of action of these compounds.

Neurochemical and molecular characterization of ketamine-induced experimental psychosis model in mice.

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.

Brain region specific monoamine and oxidative changes during restraint stress.

BACKGROUND AND PURPOSE: Stress-induced central effects are regulated by brain neurotransmitters, glucocorticoids and oxidative processes. Therefore, we aimed to evaluate the simultaneous alterations in the monoamine and antioxidant systems in selected brain regions (frontal cortex, striatum and hippocampus) at 1 hour (h) and 24h following the exposure of restraint stress (RS), to understand their initial response and possible crosstalk. METHODS AND RESULTS: RS (150 min immobilization) significantly increased the dopamine levels in the frontal cortex and decreased them in the striatum and hippocampus, with selective increase of dopamine metabolites both in the 1h and 24h RS groups compared to control values. The serotonin and its metabolite levels were significantly increased in both time intervals, while noradrenaline levels were decreased in the frontal cortex and striatum only. The activities of superoxide dismutase, glutathione peroxidase and the levels of lipid peroxidation were significantly increased with significant decrease of glutathione levels in the frontal cortex and striatum both in the 1h and 24h RS groups. There was no significant change in the catalase activity in any group. In the hippocampus, the glutathione levels were significantly decreased only in the 1h RS group. CONCLUSIONS: Our study implies that the frontal cortex and striatum are more sensitive to oxidative burden which could be related to the parallel monoamine perturbations. This provides a rational look into the simultaneous compensatory central mechanisms operating during acute stress responses which are particular to precise brain regions and may have long lasting effects on various neuropathological alterations.

Ameliorative effects of Panax quinquefolium on experimentally induced reflux oesophagitis in rats.

BACKGROUND & OBJECTIVES: Reflux oesophagitis (RE), is one of the most prevalent chronic gastrointestinal disorders commonly referred to as gastroesophageal reflux disease (GERD) and requires long term therapy. The present study was designed to investigate the protective effects of Panax quinquefolium (PQ), administered with variable doses, on experimentally induced reflux oesophagitis (RE) in rats. METHODS: Forty two female Sprague-Dawley (180-220 g) rats were randomly divided to receive standardized root powder of PQ (50-200mg/kg, po), standard anti-reflux (omeprazole, 5 mg/kg, ip) and anti-oxidant (α-tocopherol, 16 mg/kg, po). After 45 min drug pretreatment, RE was produced in rats by simultaneous ligation of the pyloric end and forestomach. Several parameters, including macroscopic lesion index, glutathione system, lipid peroxidation (LPO) and tissue myeloperoxidase (MPO) activity were measured. Alterations in ICAM-1, CINC-2 and MCP-1 gene expression were examined through reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: PQ significantly attenuated the severity of the macroscopic signs of RE-induced tissue damage, replenished the depleted GSH level and reduced the RE-associated LPO levels dose dependently. In contrast, omeprazole though effectively improved the mucosal damage, it failed to bring significant attenuation of RE-associated changes in LPO, GSH level and MPO activity. α-Tocopherol significantly ameliorated RE-induced tissue injury and improved LPO level and GSH/GSSG ratio but failed to counteract RE-induced MPO activity. PQ at dose of 100 mg/kg significantly downregulated ICAM-1 and CINC-2 expression whereas it showed no effect over MCP-1 expression. INTERPRETATION & CONCLUSIONS: The present data indicate that PQ protects against RE-induced oesophageal damage via a mechanism that inhibits the influx of inflammatory cell to oesophagus and a consequence excessive oxidative load, opening the avenue to its promising protective role in patients with gastroesophageal reflux disease (GERD).

Novel Ocimumoside A and B as anti-stress agents: modulation of brain monoamines and antioxidant systems in chronic unpredictable stress model in rats.

Therapies targeting central stress mechanisms are fundamental for the development of successful treatment strategies. Ocimum sanctum (OS) is an Indian medicinal plant traditionally used for the treatment of various stress-related conditions. Previously, we have isolated and characterized three OS compounds; Ocimarin, Ocimumoside A and Ocimumoside B. However, their role in modulating chronic stress-induced central changes is unexplored. Thus, in the present study the efficacy of these OS compounds have been evaluated on the chronic unpredictable stress (CUS)-induced alterations in the monoaminergic and antioxidant systems in the frontal cortex, striatum and hippocampus, along with the changes in the plasma corticosterone levels. CUS (two different types of stressors daily for seven days) resulted in a significant elevation of plasma corticosterone level, which was reversed to control levels by pretreatment with Ocimumoside A and B (40 mg/kg p.o.), while Ocimarin showed no effect. The levels of NA, DA and 5-HT were significantly decreased in all the three brain regions by CUS, with a selective increase of DA metabolites. A significant decrease in the glutathione (GSH) content, the activities of superoxide dismutase and catalase with a significant increase in the glutathione peroxidase activity and lipid peroxidation was observed in all the three regions of the brain by CUS. The OS compounds alone did not cause any significant change in the baseline values of these parameters. However, Ocimumoside A and B (40 mg/kg body p.o.) attenuated these CUS-induced alterations with an efficacy similar to that of standard anti-stress (Panax quinquefolium; 100 mg/kg p.o.) and antioxidant (Melatonin; 20 mg/kg i.p.) drugs. While, Ocimarin failed to modulate these CUS-induced alterations. Therefore, this is the first report which identified the anti-stress activity of novel Ocimumoside A and B at the level of central monoamines and antioxidant properties, implicating their therapeutic importance in the prevention of stress-related disorders.

Gastroprotective effect of anti-cancer compound rohitukine: possible role of gastrin antagonism and H(+) K (+)-ATPase inhibition.

The present study was designed to evaluate the anti-ulcerogenic properties of an alkaloid chromane, rohitukine from Dysoxylum binectariferum. Anti-ulcer potential of rohitukine was assessed in cold restrained, pyloric ligated and ethanol induced ulcers in rats. In addition, rohitukine was tested in vitro for H(+) K(+)-ATPase inhibitory activity in gastric microsomes. Moreover, we studied the role of rohitukine on the cytosolic concentration of Ca(2+) in parietal cell-enriched cell suspension in order to ascertain its mechanism of action. Cytoprotective activity was evaluated through PGE(2) level. Rohitukine significantly attenuated the ulcers in cold restraint ulcer (CRU) model in a dose-related manner. Moreover, it significantly lowered the free acidity and pepsin activity in pyloric ligated rats while improved the depleted level of mucin. Furthermore, rohitukine significantly reversed the cold restrained-induced increase in gastrin level. Our in vitro study revealed that rohitukine moderately inhibited the microsomal H(+) K(+)-ATPase activity with respect to positive control omeprazole. Furthermore, rohitukine potently antagonized the gastrin-elicited increase in cytosolic Ca(2+) level in parietal cell-enriched suspension. In ethanol-induced gastric lesions in rats, rohitukine significantly inhibited the formation of erosions and increased PGE(2) content showing more potency than reference drug sucralfate. Our results thus suggest that rohitukine possess significant anti-ulcer and anti-gastrinic activity in rats. It is likely that gastro-protective influences of rohitukine are dependent partly on its acid-lowering potential and partly on cytoprotective property. The acid-reducing effect of rohitukine might be attributed to its lowering effect on gastrin production and/or antagonism of gastrin-evoked functional responses of parietal cells. Thus, rohitukine represent a useful agent in the treatment of peptic ulcer disease.