Chronic administration of St. John’s Wort attenuates alcohol intake and brain indoleamine 2, 3-dioxygenase activity in mice

Present study aims to elucidate the effects of chronic administration of St. John's Wort [SJW] [500mg/kg] on brain tryptophan [TRP] metabolites and indoleamine 2-3 dioxygenase [IDO] activity in alcohol treated mice. Locally bred Albino BALB/c mice, weighing 20-25g were divided into three groups [untreated controls, Alcohol, Alcohol +Drug] having 6 mice in each. Freshly prepared ethanol solution was administered in drinking water in the proportion of 5% for three days or 8% for 3 weeks to two groups. After 3 weeks drug group was treated with SJW [dissolved in ethanol: saline 1:3 v/v] at a dose of 500mg/kg was administered orally for 1 week. During treatment alcohol intake was monitored .In present finding chronic administration of SJW significantly reduced ethanol intake by 78.6% [P<0.001] in mice. Data analyzed by student's t-test indicates that SJW remarkably reduce kynurenine [KYN] by 60.9% [P<0.001] and KYN/TRP ratio [IDO] activity] by 70.9% [P<0.001] in brain. Low serotonin level promotes alcohol intake. Present results suggest that SJW decreases alcohol intake by inhibiting IDO thereby shifting TRP catabolism towards serotonin synthesis

Phytochemical, antioxidant and antimicrobial activities of flowers of phlox drummondii

The extracts and fractions of flowers of Phloxdrum mondii were evaluated for antimicrobial and antioxidant activities. Their purification resulted in the isolation of four known constituents of which uracil and 2-methyl-1,2,3,4- butantetrol have not been obtained previously from any specie of the genus Phlox, while isolation of the flavonoid glycosides [1] and [2] have been reported from the flowers of the plant. Among all the samples PhFC and its fraction PhFCM showed significant activity against both bacteria and fungi. Flavonoid glycoside O-rhamnosyl-6-C-xylosylapigenin 1 and O-rhamnosyl- 6- C-xylosylluteolin 2 demonstrated antioxidant activity which were of same magnitude [IC50 42.67 +/- 4.99 micro g/ml and 46.33 +/- 6.65 micro g/ml, respectively]. Thereby, suggesting that the presence or absence of hydroxyl group at position C-3' does not play a significant role in said activity in this case. Interestingly, the mixture of 1 and 2 apparently showed synergism as reflected by 45% improvement in antioxidant activity as compared to the individual values obtained for either 1 or 2

Serotonergic activity and hypothalamic-pituitary-adrenal axis response in alcohol administered and subsequently withdrawn rats

Present study aims to depict the role of serotonergic pathways in discrete brain areas [hypothalamus, amygdala, and hippocampus] and their interaction with hypothalamic pituitary adrenal [HPA] axis in alcohol dependence and subsequent withdrawal syndrome in rats. Albino Wistar rats were fed a liquid diet containing alcohol for 4 weeks. Matched control rats were fed isocaloric amounts of the alcohol-free liquid diet, in which the alcohol contribution was substituted with maltose-dextrin. Brain regional tryptophan, 5-hydroxytryptamine [5-HT], 5-Hydroxyindoleacetic acid [5-HIAA] concentrations were determined using high performance liquid chromatography with flourimetric detector. Serum corticosterone was determined spectrofluorimetrically. Data analysis showed that there was significant increase in tryptophan [hippocampus], 5-HT [hippocampus and amygdale]and 5-HT turnover in all the three regions examined when alcohol administered rats were compared with matched controls. In contrast withdrawal from alcohol decreased brain tryptophan, 5-HT and its turnover. It is concluded that the prolong alcohol use boost functions of serotonergic neuronal pathways, in particular, hypothalamus that regulate HPA-axis function and develop tolerance and adaptation. In addition, withdrawal from alcohol exacerbates serotonergic functions that results in failure to suppress corticosterone levels and hence induce low mood states and other signs and symptoms of alcohol withdrawal syndrome

Correlation of affective disorder with BMI in reproductive and menopausal age women

OBJECTIVE: To correlate affective disorder with the body mass index [BMI] in reproductive and menopausal age women

STUDY DESIGN: Cross-sectional study

SETTING: Consultant Psychiatric Clinic DURATION: From 1[st] March 2012 to 30[th] November 2014

METHOD: Women visiting the psychiatric Consultation Clinic were grouped as reproductive and menopausal aged group in relation to their diagnosis as depressed or bipolar affective disorders as per ICD-10 criteria. Their BMI calculated by weight in kilograms divided by the square of the height in meters square [kg/m[2]

RESULTS: Total 224 consecutive women with prior written and oral consent were included in this study. It was found that menopausal women had greater BMI values as compared to the women in reproductive age. Similarly in the subcategories of BMI classified as underweight, normal, overweight and obese, the menopausal group significantly correlated with BMI having higher values. The BMI did not correlate with the occurrence of affective disorders, be it depression or bipolar disorder, even in the subcategories

CONCLUSION: Thus, it can be concluded that owing to the biochemical and neurochemical impact, BMI may affect the mental status of women. Further on present results can be helpful in the treatment of affective disorder patients, emphasizing on nutrition and exercise

Assessment of cardiovascular disease risk in depressed women of reproductive and menopausal age

It is well documented that depression increases the risk of cardiovascular disease [CVD]. Women of age 55 and younger with depression are more likely to have CVD. The present study aims to investigate CVD risk in depressed women of reproductive age [RA] and menopausal age [MA]. Adult women of RA and MA were divided in to two groups; healthy and depressed. Women were screened for depression [ICD-10 criteria] at outpatients department of local psychiatric hospital. Fasting serum cortisol, estradiol and lipid profile levels were determined. Data was analyzed using two-way ANOVA followed by Newman's Keuls q-test. Total cholesterol [TC], low-density lipoproteins [LDL] and triglycerides [TGs] were raised in MA women however high density lipoprotein [HDL] and estradiol were lower as compared to RA women. Depressed RA women showed increased TC, LDL and HDL but decreased estradiol as compared to healthy women of similar age group. MA depressed women showed increased TC and LDL but decreased HDL and estradiol as compared to healthy controls. We found that MA depressed women had low HDL and estradiol as compared to RA depressed women. Circulating cortisol levels were increased in both depressed RA and MA women compared to respective healthy controls. Low HDL/LDL ratio was found in both healthy and depressed MA women when compared with respective RA women. A significant negative correlation of estradiol and cortisol was found in depressed RA women. It is concluded that low HDL/LDL ratio and hypercortisolemia in both healthy and depressed MA women make them more vulnerable to CVD

Effects of smokeless dipping tobacco [Naswar] consumption on antioxidant enzymes and lipid profile in its users

Dipping tobacco, traditionally referred to as moist snuff, is a type of finely ground, moistened smokeless tobacco product. Naswar is stuffed in the floor of the mouth under the lower lip, or inside the cheek, for extended periods of time. Tobacco use causes dyslipidemia and also induces oxidative stress, leading to alteration in levels of antioxidant enzymes. Dyslipidemia and oxidative stress in turn play a vital role in the development of cardiovascular disease [CVD]. Studies conducted on smokeless tobacco products reveal contradictory findings regarding its effects on lipid profile and antioxidant enzymes. As use of Naswar is quite common in Pakistan, the current study aimed to evaluate levels of the antioxidant enzymes viz glutathione per oxidase [GPx] and super oxide dismutase [SOD], alongside lipid profile parameters such as total cholesterol, triglycerides, High density lipoprotein cholesterol [HDL-C] and low density lipoprotein cholesterol [LDL-C] to assess the risk of adverse cardiovascular events in Naswar users.90Healthy males aged 16-43 years, who consumed Naswar daily, were selected for the study, alongside 68 age-matched non-tobacco users as controls. Both GPx and SOD levels as well as serum HDL-C were significantly reduced [P<0.01] in Naswar users, whereas serum total cholesterol, LDL-C, triglycerides and LDL-C/HDL-C ratio were significantly increased [P<0.01] in Naswar consumers compared to controls. Our findings indicate deleterious effects of Naswar usage on health by causing altered lipid profile and antioxidant enzymes thereby placing its consumers at an increased risk of cardiovascular disease

St. John's Wort increases brain serotonin synthesis by inhibiting hepatic tryptophan 2, 3 dioxygenase activity and its gene expression in stressed rats

We aimed to investigate the effects of herbal St. John's Wort [SJW] on transcriptional regulation of hepatic tryptophan 2, 3 - dioxygenase [TDO] enzyme activity and brain regional serotonin [5-HT] levels in rats exposed to forced swim test [FST]

TDO mRNA expression was quantified using real-time reverse transcription polymerase chain [RT-PCR] reaction and brain regional indoleamines were determined by high performance liquid chromatography coupled to fluorescence detector. Behavioral analysis shows significant reduction in immobility time in SJW [500mg/kg/ml] administered rats. It was found that pretreatment of SJW to rats did not prevent stress-induced elevation in plasma corticosterone levels however it increases serotonin synthesis by virtue of inhibiting hepatic TDO enzyme activity and its gene expression, ascertaining the notion that there exists an inverse relationship between hepatic TDO enzyme activity and brain 5-HT. The drug also decreases serotonin turnover in all the brain areas [hypothalamus, hippocampus amygdale] in stressed rats endorsing its monoamine oxidase inhibition property. Inhibition of TDO enzyme activity and its gene expression by the drug provides new insights for the development of therapeutic interventions for stress related mental illnesses

Docking studies of antidepressants against single crystal structure of tryptophan 2, 3-dioxygenase using Molegro Virtual Docker software

Tryptophan 2, 3-dioxygenase [TDO] a heme containing enzyme found in mammalian liver is responsible for tryptophan [Trp] catabolism. Tip is an essential amino acid that is degraded in to N-formylkynurenine by the action of TDO

The protein ligand interaction plays a significant role in structural based drug designing. The current study illustrates the binding of established antidepressants [Ads] against TDO enzyme using in-silico docking studies. For this purpose, Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Seproxetine, Citalopram, Moclobamide, Hyperforin and Amoxepine were selected. In-silico docking studies were carried out using Molegro Virtual Docker [MVD] software. Docking results show that all ADs fit well in the active site of TDO moreover Hyperforin and Paroxetine exhibited high docking scores of-152.484k cal/mol and -139.706k cal/mol, respectively. It is concluded that Hyperforin and Paroxetine are possible lead molecules because of their high docking scores as compared to other ADs examined. Therefore, these two ADs stand as potent inhibitors of TDO enzyme

Acute effects of serotonergic antidepressants on tryptophan metabolism and corticosterone levels in rats

The aim of present study is to see the effects of antidepressants in relation to tryptophan metabolism and disposition and to know whether they share any common mechanism of action in this regard. These are the monoamine oxidase inhibitor [moclobemide], atypical tricyclic [tianeptine], selective serotonin reuptake inhibitors [SSRIs] namely sertraline and citalopram and an herbal St John's Wort [SJW]. Liver tryprophan pyrrolase activity, serum tryptophan, corticosterone and brain indoles were determined after drug administration in Albino Wistar rats at a dose of 10mg/kg. All five antidepressants inhibited tryptophan pyrrolase activity. Serum total tryptophan concentrations were increased by 19% and 33% by tianeptine and moclobemide respectively, however 34% decrease in total tryptophan was observed after SJW administration. Free tryptophan was increased by all the drugs being maximum [65% P<0.001] by sertraline and minimum [15%, P<0.05] by tianeptine. Corticosterone levels were significantly [P<0.01] decreased by 52 and 58 percent by citalopram and St John's Wort respectively. By contrast an increase by 16% was observed by tianeptine. It was also observed that all the drugs increase brain tryptophan by 21-61 percent but increases in 5-hydroxytryptamine [5-HT] were observed only by two drugs that is moclobemide and SJW, however in comparison increases were greater [68%] after SJW administration. 5-hydroxyindoleacetic acid [5HIAA] concentrations were increased by 45-64% by all other drugs except tianeptine and moclobemide. It is concluded that attenuation of peripheral tryptophan metabolism and elevation of brain tryptophan contributes to the mechanism of action of antidepressants of different classes and pharmacological profile tested

St. John's Wort modulates brain regional serotonin metabolism in swim stressed rats

Present study has investigated acute effects of Saint Johns Wort [SJW, 500 mg/kg] administration on behavioral, neuroendocrine responses and serotonergic activity following forced swim test [FST] exposure in rats. The results show that SJW increased swimming and climbing behaviour of rats during FST exposure. Swim stress produced significant reduction in serum total tryptophan [P < 0.01], increase in corticosterone [P < 0.01] and 5-hydroxytryptamine [serotonin, 5-HT] turnover in hypothalamus by 100% [P < 0.01], amygdala by 148% [P < 0.01], and hippocampus by 41% [P < 0.05] when compared with unstressed saline injected group. SJW in swim stressed rats when compared with saline injected stressed rats altered neither lowered serum tryptophan nor enhanced HPA axis response, however 5HT was found to be increased by 110% [P < 0.01], 163% [P < 0.01] and 172% [P < 0.01], in hypothalamus, amygdala and hippocampus respectively. 5-hydroxyindoleacetic acid [5HIAA] was also found to be increased in hypothalamus by 74% [P < 0.01], amygdala by 45% [P < 0.01] and hippocampus by 143.5% [P < 0.01]. Further SJW administration in unstressed rats showed decrease in tryptophan [P < 0.01], increase in corticosterone [P < 0.01], 5HT was found to be decreased in hypothalamus [47%, P < 0.01] and in amygdala [13%, P < 0.05] with no change in hippocampus, while 5HIAA was found increased in hypothalamus by 58%[P < 0.01], amygdale by 203% [P < 0.01] and hippocampus by 171% [P < 0.01]. The data shows that SJW affects circulating tryptophan and corticosterone in absence of conditioned stress but not in its presence. In conclusion, SJW increases intraneuronal 5HT metabolism but inhibits its release under adverse conditions proving its anxiolytic property. Thus, these effects produced by the SJW add to our understanding of the interactions between SJW and stress induced behavioral, neuroendocrine and serotonergic alterations

Brain trptophan metabolism remained unaltered in restraint stressed rats following fluoxetine administration

Effects of two hours immobilization stress on tryptophan [Tp] metabolism in rats was studied following fluoxetine-HCl [20mg/kg] administration. After 2hr immobilization stress there was no effect on peripheral liver Tp metabolism but there was marked increase in brain Tp metabolism leading to increases in 5-HT [5-Hydroxy tryptamine] synthesis and turn over. Rats subjected to 2hrs immobilization stress immediately after fluoxetine-HCl [20mg/kg] administrations show significant increases in holo and total Tp pyrrolase enzyme activities leading to decreased serum total Tp concentrations. Brain Tp and 5-HT remain unchanged but 5-hydroxy indole acetic acid [5-HIAA] concentration was significantly increased when compared to fluoxetine injected non-immobilized rats. Administration of fluoxetine-HCl [20mg/kg] inhibited holo and total Tp pyrrolase enzyme activities when compared to saline injected rats and ultimately increases liver Tp concentrations. Although serum total Tp remained un- changed but brain Tp and 5-HT concentrations were significantly increased. It is therefore concluded that pre-treatment of rats with fluoxetine-HCl did not alter conditioned stress induced change in brain Tp metabolism. Future studies on chronic administration of the drug will be fruit full to investigate its effects on Tp metabolism in conditioned stress

Gender based response to fluoxetine hydrochloride medication in endogenous depression

To determine the gender based response to fluoxetine HCl medication in relation to tryptophan metabolism in depressed patients. Design: A comparative, analytical study. Place and Duration of Study: Clinical Biochemistry and Psychopharmacology Research Unit, Department of Biochemistry, University of Karachi during the year 2002 to 2003. Subjects and Sixteen adults depressed patients who were not having any other major comorbidity were selected from the outpatients department of local psychiatric clinic for the study. They were subjected to a semi-structured interview for associated clinical characteristics and diagnosis of depression according to ICD-10 criteria. A control group of normal health male and female individuals was identified for comparison with the depressed group.All the depressed patients were treated with fluoxetine hydrochloride [Prozac 20 mg/day] for four weeks. Healthy individual's data was compared with the depressed group and evaluated for gender based response to fluoxetine HCl medication. Significant decreases were found in total tryptophan concentrations [33%, p<0.01,56%, p<0.01] in depressed male and female patients respectively, in contrast, serum cortisol levels were increased by 68% and 98% in male and female depressed patients respectively as compared to healthy controls. Significant increases [23%, p<0.05] in albumin levels were found in females only. Four weeks treatment of male and female depressed group by Fluoxetine HCL [Prozac] 20 mg/kg/day, increased serum total tryptophan concentrations significantly by 32% [p<0.05] in males and by 83% [p<0.01] in females. Serum-free tryptophan concentrations were increased by 22% [p<0.05] in males only. In contrast serum cortisol concentrations were decreased by 31% [p<0.01] and 45.35% [p<0.01] in males and females respectively. Increases in tryptophan and decreases in cortisol concentrations were greater in females which may contribute to better response of the drug in females

Inhibition of tryptophan-pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats

To investigate in-vitro as well as in-vivo effects of various doses of fluoxetine [SSRI] on tryptophan metabolism in rats. Design: A pre-clinical study. Place and Duration of Study: Clinical Biochemistry Research Laboratory, Department of Biochemistry, University of Karachi. The investigation was carried out during 2000 to 2001. Subjects and Male Wistar rats [150-200 g body wt] were selected and divided into control and test groups [n = 5] for comparison. In in-vitro [10 - 1000mM] as well in-vivo [0.5 ' 30 mg/kg body wt.] studies, fluoxetine showed a statistically significant inhibition of rat liver tryptophan pyrrolase [tryptophan-2,3-dioxygenase; EC 1.13.11.11] activity. Significant increases were noted at 10 and 30 mg/kg doses in brain, serum [total and free] and liver L-tryptophan concentrations. Similarly, serum non-estrified free fatty acids showed a significant increase at both doses. There was no effect on serum glucose and albumin concentrations. It is suggested that major mechanism of action of fluoxetine is that of elevating brain tryptophan concentration and hence 5-HT synthesis by increasing the availability of circulating tryptophan to the brain secondarily to inhibition of major tryptophan degrading enzyme, hepatic tryptophan pyrrolase. It is assumed that fluoxetine inhibits the binding of apoenzyme form of tryptophan pyrrolase with its cofactor haem. The results are discussed in relation to possible involvement of disturbed hepatic tryptophan metabolism in depressive illness

Injected monosodium glutamate increases holotryptophan pyrrolase activity and plasma corticosterone levels more in male than female rats

Monosodium glutamate [MSG] injected intra - peritoneally at doses 4 g/kg increased holotryptophan pyrrolase activity significantly by 61.6% in male rats. The increases were smaller [24%] and non- significant in females. Apotryptophan was decreased by 61% and comparably in the two sexes. Cumulative effect on total enzyme activity was a reduction of 37.5% in female rats. A decrease of 20.6% in male rats was not significant. Plasma levels of corticosterone were increased significantly in male but not in female rats. The sex differences are explained in terms of female hormones being effected by MSG administration and higher circulating MSG - induced corticosterone levels being involved in the enhancement of holotryptophan pyrrolase activity in male rats. Plasma total tryptophan levels were increased due to an inhibition of total tryptophan pyrrolase activity in female but not in male. Plasma free tryptophan concentrations were decreased in both sexes