Anti-stress activity of Indian Hypericum perforatum L

Indian Hypericum perforatum (IHp) was investigated on a 14-day mild, unpredictable and inescapable foot shock stress (FSS) induced perturbations in behaviour (depression), suppressed male sexual behaviour and cognitive dysfunction in albino rats. Gastric ulceration, and adrenal gland and spleen weights, were also used as the stress indices. Panax ginseng (PG) was used as the standard adaptogenic agent for comparison. FSS induced marked gastric ulceration, significant increase in adrenal gland weight with concomitant decrease in spleen weight. Chronic stress also suppressed male sexual behaviour, induced behavioural depression (Porsolt's swim despair test and learned helplessness test) and cognitive dysfunction (attenuated retention of learning in active and passive avoidance tests). All these FSS induced perturbations were attenuated dose dependently by IHp (100 and 200 mg/kg, po) and PG (100 mg/kg, po). The results indicate that IHp has significant anti-stress activity, qualitatively comparable to PG, against a variety of behavioural and physiological perturbations induced by chronic stress, which has been proposed to be a better indicator of clinical stress than acute stress, and may indicate adaptogenic activity.     

Adaptogenic activity of Siotone, a polyherbal formulation of Ayurvedic rasayanas

Siotone (ST) is a herbal formulation comprising of Withania somnifera, Ocimum sanctum, Asparagus racemosus, Tribulus terristris and shilajit, all of which are classified in Ayurveda as rasayanas which are reputed to promote physical and mental health, improve defence mechanisms of the body and enhance longevity. These attributes are similar to the modern concept of adaptogenic agents, which are, known to afford protection of the human physiological system against diverse stressors. The present study was undertaken to investigate the adaptogenic activity of ST against chronic unpredictable, but mild, footshock stress induced perturbations in behaviour (depression), glucose metabolism, suppressed male sexual behaviour, immunosuppression and cognitive dysfunction in CF strain albino rats. Gastric ulceration, adrenal gland and spleen weights, ascorbic acid and corticosterone concentrations of adrenal cortex, and plasma corticosterone levels, were used as the stress indices. Panax ginseng (PG) was used as the standard adaptogenic agent for comparison. Additionally, rat brain levels of tribulin, an endogenous endocoid postulated to be involved in stress, were also assessed in terms of endogenous monoamine oxidase (MAO) A and MAOB inhibitory activity. Chronic unpredictable footshock induced marked gastric ulceration, significant increase in adrenal gland weight and plasma corticosterone levels, with concomitant decreases in spleen weight, and concentrations of adrenal gland ascorbic acid and corticosterone. These effects were attenuated by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.), administered once daily over a period of 14 days, the period of stress induction. Chronic stress also induced glucose intolerance, suppressed male sexual behaviour, induced behavioural depression (Porsolt's swim despair test and learned helplessness test) and cognitive dysfunction (attenuated retention of learning in active and passive avoidance tests), and immunosuppression (leucocyte migration inhibition and sheep RBC challenged increase in paw oedema in sensitized rats). All these chronic stress-induced perturbations were attenuated, dose-dependently by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.). Chronic stress-induced increase in rat brain tribulin activity was also reversed by these doses of ST and by PG. The results indicate that ST has significant adaptogenic activity, qualitatively comparable to PG, against a variety of behavioural, biochemical and physiological perturbations induced by unpredictable stress, which has been proposed to be a better indicator of clinical stress than acute stress parameters. The likely contribution of the individual constituents of ST in the observed adaptogenic action of the polyherbal formulation, have been discussed.     

A premature increase in circulating cortisol suppresses expression of 11beta hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid in the adrenal of the fetal sheep

We have investigated the effect of intrafetal cortisol administration, before the normal prepartum cortisol surge, on the expression of 11beta hydroxysteroid dehydrogenase (11betaHSD) type 2 mRNA in the fetal adrenal. We also determined whether increased fetal cortisol concentrations can stimulate growth of the fetal adrenal gland or increase expression of adrenal steroidogenic enzymes. Cortisol (hydrocortisone succinate: 2.0-3.0 mg in 4.4 ml/24 h) was infused into fetal sheep between 109 and 116 days of gestation (cortisol infused; n = 12), and saline was administered to control fetuses (saline infused; n = 13) at the same age. There was no effect of cortisol infusion on the fetal adrenal:body weight ratio (cortisol: 101.7 +/- 5.3 mg/kg; saline: 108.2 +/- 4.3 mg/kg). The ratio of adrenal 11betaHSD-2 mRNA to 18S rRNA expression was significantly lower, however, in the cortisol-infused group (0.75 +/- 0.02) compared with the group receiving saline (1.65 +/- 0.14). There was no significant effect of intrafetal cortisol on the relative abundance of adrenal CYP11A1, CYP17, CYP21A1, and 3betaHSD mRNA. A premature elevation in fetal cortisol therefore resulted in a suppression of adrenal 11betaHSD-2. Increased intra-adrenal exposure to cortisol at this stage of gestation is, however, not sufficient to promote adrenal growth or steroidogenic enzyme gene expression.     

Effect of chronic cadmium treatment on rat adrenal catecholamines.

Daily intraperitoneal injection of cadmium chloride (1 mg/kg) for 45 days significantly increased adrenal weights and augmented the levels of adrenal norepinephrine and epinephrine as well as the activity of adrenal tyrosine hydroxylase. Discontinuation of the heavy metal treatment for 28 days, in rats previously injected with cadmium for 45 days, restored the activity of tyrosine hydroxylase as well as the amount of norepinephrine and epinephrine. In contrast, adrenal weights were restored only partially following the withdrawal of cadmium treatment. Evidence indicates that the changes in adrenal catecholamine metabolism may be the result of stress induced by chronic exposure to this heavy metal. In addition, some of the untoward effects such as hyperglycemia and arterial hypertension seen during cadmium toxicity might be related to increased synthesis of epinephrine in adrenal glands.     

Pre-translational induction of pentoxyresorufin O-depentylase by pyridine.

Pentoxyresorufin O-depentylase activity, mainly associated with phenobarbital-inducible cytochrome P450IIB1 (designated CYP2B1), was increased after a single treatment of pyridine (250 mg/kg, i.p.), and further increased by repeated treatments for 5 days. The catalytic activity and immunoreactive protein of CYP2B recognized by polyclonal antibodies were significantly induced by a relatively high dose of pyridine (250 mg/kg, i.p.) while ethanol-inducible cytochrome P450IIE1 (CYP2E1) could be induced by a low dosage (25 mg/kg, i.p.). Unlike CYP2E1 induction without changing its mRNA level, the induction of CYP2B by pyridine was accompanied by an elevation of its mRNA, indicating a pre-translational activation of this enzyme. These results indicate that pyridine induces various isozymes of cytochromes P450 by different induction mechanisms.     

Modulation of hepatic and renal drug metabolizing enzyme activities in rats by subchronic administration of farnesol

Farnesol demonstrates antitumor activity in several animal models for human cancer and was being considered for development as a cancer chemopreventive agent. This study was performed to characterize the effects of minimally toxic doses of farnesol on the activity of phase I and II drug metabolizing enzymes. CD((R)) rats (20/sex/group) received daily gavage exposure to farnesol doses of 0, 500, or 1000 mg/kg/day for 28 days; 10 rats/sex/group were necropsied at the termination of farnesol exposure; remaining animals were necropsied after a 28-day recovery period. No deaths occurred during the study, and farnesol had no significant effects on body weight, food consumption, clinical signs, or hematology/coagulation parameters. Modest but statistically significant alterations in several clinical chemistry parameters were observed at the termination of farnesol exposure; all clinical pathology effects were reversed during the recovery period. At the termination of dosing, the activities of CYP1A, CYP2A1-3, CYP2B1/2, CYP2C11/12, CYP2E1, CYP3A1/2, CYP4A1-3, CYP19, glutathione reductase, NADPH/quinone oxidoreductase and UDP-glucuronosyltransferase were significantly increased in the livers of farnesol-treated rats; farnesol also increased the activity of glutathione S-transferase in the kidney. The effects of farnesol on hepatic and renal enzymes were reversed during the recovery period. At the end of the dosing period, increases in absolute and relative liver and kidney weights were seen in farnesol-treated rats. These increases may be secondary to induction of drug metabolizing enzymes, since organ weight increases were not associated with histopathologic alterations and were reversed upon discontinuation of farnesol exposure. Administration of farnesol at doses of up to 1000 mg/kg/day induced reversible increases in the activities of several hepatic and renal drug metabolizing enzymes in rats, while inducing only minimal toxicity. It is concluded that non-toxic or minimally toxic doses of farnesol could alter the metabolism, efficacy, and/or toxicity of drugs with which it is co-administered.     

Induction of rat hepatic drug metabolizing enzymes by dimethylcyclosiloxanes

Low molecular weight dimethylcyclosiloxanes (DMCS) are important precursors in the synthesis of polydimethysiloxane polymers widely used in industry, and in medical and personal care products. The objective of this study was to characterize the ability of two DMCS, octamethylcyclosiloxane (D4) and decamethylcyclopentasiloxane (D5) to induce drug metabolizing enzymes in rats. Male and female Sprague-Dawley rats were administered 1, 5, 20, or 100 mg/kg D4 or D5 in corn oil daily by gavage for 4 days. Changes in the levels of activity and/or immunoreactivity of CYP1A1/2, CYP2B1/2, CYP3A1/2 and NADPH cytochrome P450 reductase in liver microsomes were examined. Significant increases were observed in the liver to body weight ratio in female rats administered either D4 or D5 at doses > or = 20 mg/kg. Increases in the liver to body weight ratio were observed in male rats treated with > or = 100 mg/kg D5 but not with D4. Relatively large increases in CYP2B1/2 enzymatic activity and immunoreactive protein were observed with increasing concentrations of both D4 and D5. Significant increases in 7-pentoxyresorufin O-depentylase (PROD) activity were also detected in male and female rats given D4 at doses > or = 5 mg/kg. D5 increased PROD activity in male rats at doses > or = 20 mg/kg and in female rats at doses > or = 5 mg/kg. 7-Ethoxyresorufin O-deethylase (EROD) activity was increased in both male and female rats receiving > or = 20 mg/kg D4 or > or = 5 mg/kg D5; however, no changes were detected in CYP1A1/2 immunoreactive protein in rats of either sex. D4 and D5 caused significant increases in CYP3A1/2 immunoreactive protein in only male rats treated with 100 mg/kg of either compound. However, significant increases were detected in CYP3A1/2 immunoreactive protein in female rats at D4 doses > or = 20 mg/kg and D5 doses > or = 5 mg/kg. Induction of NADPH cytochrome P-450 reductase immunoreactive protein was observed with D4 in female rats and in both male and female rats with D5. Induction of CYP2B/1/2, CYP3A1/2 and NADPH cytochrome P450 reductase was observed in rats treated with 50 mg/kg phenobarbital by intraperitoneal injection. Maximal CYP2B induction detected with D4 was approximately 50% of the increase observed with phenobarbital. In summary, D4 and D5 induced CYP2B1/2 in adult rat liver in a manner similar to that observed with phenobarbital; however, differences were observed between D4 and D5 in their ability to induce CYP3A1/2 and NADPH cytochrome P450 reductase. Female rats were more sensitive to the inductive properties of low doses of both DMCS than male rats whereas male rats were more responsive to phenobarbital induction.     

Beta-agonist-induced alterations in organ weights and protein content: comparison of racemic clenbuterol and its enantiomers

Clenbuterol is a relatively selective beta2-adrenergic partial agonist that has bronchodilator activity. This drug has been investigated as a potential countermeasure to microgravity- or disuse-induced skeletal muscle atrophy because of presumed anabolic effects. The purpose of this study was to: 1) analyze the anabolic effect of clenbuterol's (-)-R and (+)-S enantiomers (0.2 mg/kg) on muscles (cardiac and skeletal) and other organs; and 2) compare responses of enantiomers to the racemate (0.4 mg/kg and 1.0 mg/kg). Male Sprague Dawley rats were treated with: a) racemic clenbuterol (rac-clenbuterol, 0.4 or 1.0 mg/kg); b) enantiomers [clenbuterol (-)-R or (+)-S]; or c) vehicle (1.0 mL/kg buffered saline). Anabolic activity was determined by measuring tissue mass and protein content. HPLC teicoplanin chiral stationary phase was used to directly resolve racemic clenbuterol to its individual enantiomers. In skeletal muscle, both enantiomers had equal anabolic activity, and the effects were muscle- and anatomic region-specific in magnitude. Although the enantiomers did not affect the ventricular mass to body weight ratio, clenbuterol (+)-S induced a small but significant increase in ventricular mass. Both clenbuterol enantiomers produced significant increases in skeletal muscle mass, while being less active in producing cardiac ventricular muscle hypertrophy than the racemic mixture.     

Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA

BACKGROUND: Since cyclophosphamide is metabolically activated to teratogenic acrolein and cytotoxic phosphoramide mustard by cytochrome P‐450 type 2B (CYP2B), we assessed the effects of licorice, a CYP2B inducer, on the fetal defects induced by cyclophosphamide. METHODS: Pregnant Sprague‐Dawley rats were daily administered with licorice (100 mg/kg) by gavage for 7 days, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11 mg/kg) 1 hr after the final licorice treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. RESULTS: Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 93.8, 41.1, and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities, respectively. When pre‐treated with licorice, cyclophosphamide‐induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with licorice greatly increased mRNA expression and activity of hepatic CYP2B. CONCLUSIONS: The results indicate that repeated intake of licorice may aggravate cyclophosphamide‐induced body weight loss and malformations of fetuses by upregulating CYP2B. Birth Defects Res (Part B) 92:553–559, 2011. © 2011 Wiley Periodicals, Inc.     

Induction of rat liver cytochrome P450 isoenzymes CYP 1A and CYP 2B by different fungicides, nitrofurans, and quercetin.

The genotoxic activity of environmental xenobiotics is manifested either in their direct interaction with cellular genetic material or in provoking secondary events, among which reactive oxygen species (ROS) production is a common phenomenon. Both pathways can be mediated by the activity of the cytochrome P450 monooxygenase system. We studied induction of the CYP 1A or CYP 2B monooxygenases in rat liver by the fungicides: thiram, captan, captafol, dodine and the drugs: nitrofurazone, furazolidone and the plant flavonoid: quercetin. A cytochrome P450 induction assay (CYPIA test) was used. S9 prepared from livers of rats treated with the test compounds were used to activate ethidium bromide (EtBr) (CYP 1A isoenzyme) or cyclophosphamide (CPA) (CYP 2B isoenzyme) in the Ames test.It was found that among the tested compounds, the most potent inducer of CYP 1A was furazolidone (3 x 80 mg/kg). Less potent was thiram (1 x 100mg/kg), as well as quercetin (3 x 80 mg/kg), and captafol (1 x 30 mg/kg). On the other hand, thiram (1 x 100 mg/kg), captafol (1 x 30 mg/kg), and quercetin (3 x 80 mg/kg) were most potent in the CYP 2B isoenzyme induction, while furazolidone (3 x 80 mg/kg), and nitrofurazone (3 x 80 mg/kg) appeared to be less potent in this respect. Captan and dodine (3 x 80 mg/kg) did not affect the activity of any of the cytochrome P450 isoenzymes.     

In vivo cytogenetic effects of a commercially formulated mixture of cypermethrin and quinalphos in mice

In vivo cytogenetic effects of commercially formulated cypermethrin (CYP, synthetic pyrethroid insecticide) and/or quinalphos (QUI, organophosphate insecticide), generally used in combination, were examined through chromosomal aberrations (CA) and micronucleus test (MT) in mice. Male mice were orally gavaged to a single dose of CYP/QUI commercial mixture (22, 44 or 67 mg/kg b.wt.) for 24h (CA) or 48 h (MT). Based on the concentrations of active ingredients of CYP and QUI present in the test doses of CYP/QUI mixture, mice were orally exposed to 0.66, 1.32 and 2 mg/kg of CYP or 4.4, 8.8 and 13.4 mg/kg of QUI. For reference, a group of five mice was intraperitoneally administered to cyclophosphamide (20 or 50 mg/kg) or orally gavaged to peanut oil for vehicle control. Exposure of CYP/QUI mixture inhibited the mitotic index (MI) and induced CA in a dose-dependent manner at 24 h; however, significant (p<0.01 or 0.001) frequencies of CA were observed at 44 mg/kg onwards, whereas inhibition of MI at 67 mg/kg. Independent exposure of QUI at 8.8 mg/kg onwards also significantly (p<0.01 or 0.001) inhibited MI and induced CA, whereas CYP at 2 mg/kg (highest concentration in CYP/QUI mixture) inhibited MI significantly but failed to induce CA. Chromatid breaks and fragments found to be frequent aberrations in all the test groups. Treatment of CYP/QUI mixture also induced micronucleus formation dose-dependently at 48 h, yet statistically significant (p<0.001) frequencies of micronucleated polychromatic erythrocytes (MNPCE) were observed at 44 mg/kg onwards. QUI (8.8 and 13.4 mg/kg) alone also induced significant frequencies of MNPCE, whereas frequencies of MNPCE observed with the CYP even at 2 mg/kg were comparable to that of vehicle control. Present findings indicate the genotoxicity potential of CYP/QUI mixture and suggest that the simultaneous presence of the toxic doses of CYP and QUI can lead to synergistic genotoxicity in mice and may pose mutagenic risk in human beings.     

Carbaryl-induced elevation of corticosterone level and cholinergic mechanism

Administration of a single dose (200 mg/kg, p.o.) of carbaryl to rats produced a significant rise in adrenal and plasma corticosterone levels and an increase of tyrosine alpha-ketoglutarate transaminase activity in the liver cytosol. Synaptosomal acetylcholinesterase activity of the hypothalamic and the striatal regions of rat brain was decreased by carbaryl treatment under similar conditions. Pretreatment (0.5 h) with atropine sulphate (10 mg/kg, i.p.) failed to counteract the carbaryl-induced elevation of adrenal and plasma corticosterone levels and hence the liver tyrosine alpha-ketoglutarate transaminase activity. Present results suggest that the carbaryl-induced rise in the corticosterone level in the adrenal gland and plasma is not due to a cholinergic mechanism.     

Anabolic actions of a mixed beta-adrenergic agonist on nitrogen retention and protein turnover.

Subcutaneous administration of a mixed beta-agonist induced increases in muscle (+13%) and heart (+17%) weights, which were accompanied by a reduction in back (-13%) and perirenal (-27%) fat stores in young male rats, while no changes in liver were observed. The values of nitrogen retention (mg/day) were significantly higher in the beta-agonist treated animals (+16%) as well as those of muscle DNA content (+8%). On the other hand, no statistically significant changes in muscle protein synthetic activity (g protein synthetized/g RNA) were detected (control: 13.4 vs treated: 14.6), while muscle proteolytic activity was decreased (-9%) in those rats administered with the repartitioning agent. In this context, it is suggested that the anabolic effect of metaproterenol should be attributed to a reduction in muscle protein degradation rather than to changes in protein synthesis.     

Propolis protects CYP 2E1 enzymatic activity and oxidative stress induced by carbon tetrachloride

Induction of CYP 2E1 by carbon tetrachloride (CCl₄) is one of the central pathways by which CCl₄ generates oxidative stress in hepatocytes. Experimental liver injury was induced in rats by CCl₄ to determine toxicological actions on CYP 2E1 by microsomal drug metabolizing enzymes. In this report, ethanolic extract of propolis at a dose of 200 mg/kg (po) was used after 24 h of toxicant administration to validate its protective potential. Intraperitoneal injection of CCl₄ (1.5 ml/kg) induced hepatotoxicity after 24 h of its administration that was associated with elevated malonyldialdehyde (index of lipid peroxidation), lactate dehydrogenase and γ-glutamyl transpeptidase release (index of a cytotoxic effect). Hepatic microsomal drug metabolizing enzymes of CYP 2E1 showed sharp depletion as assessed by estimating aniline hydroxylase and amidopyrine N-demethylase activity after CCl₄ exposure. Toxic effect of CCl₄ was evident on CYP 2E1 activity by increased hexobarbitone induced sleep time and bromosulphalein retention. Propolis extract showed significant improvement in the activity of both enzymes and suppressed toxicant induced increase in sleep time and bromosulphalein retention. Choleretic activity of liver did not show any sign of toxicity after propolis treatment at a dose of 200 mg/kg (id). Histopathological evaluation of the liver revealed that propolis reduced the incidence of liver lesions including hepatocyte swelling and lymphocytic infiltrations induced by CCl₄. Electron microscopic observations also showed improvement in ultrastructure of liver and substantiated recovery in biochemical parameters. Protective activity of propolis at 200 mg/kg dose was statistically compared with positive control silymarin (50 mg/kg, po), a known hepatoprotective drug seems to be better in preventing hepatic CYP 2E1 activity deviated by CCl₄. These results lead us to speculate that propolis may play hepatoprotective role via improved CYP 2E1 activity and reduced oxidative stress in living system.     

Induction of rat liver cytochrome P450 isoenzymes CYP 1A and CYP 2B by different fungicides, nitrofurans, and quercetin

The genotoxic activity of environmental xenobiotics is manifested either in their direct interaction with cellular genetic material or in provoking secondary events, among which reactive oxygen species (ROS) production is a common phenomenon. Both pathways can be mediated by the activity of the cytochrome P450 monooxygenase system. We studied induction of the CYP 1A or CYP 2B monooxygenases in rat liver by the fungicides: thiram, captan, captafol, dodine and the drugs: nitrofurazone, furazolidone and the plant flavonoid: quercetin. A cytochrome P450 induction assay (CYPIA test) was used. S9 prepared from livers of rats treated with the test compounds were used to activate ethidium bromide (EtBr) (CYP 1A isoenzyme) or cyclophosphamide (CPA) (CYP 2B isoenzyme) in the Ames test.It was found that among the tested compounds, the most potent inducer of CYP 1A was furazolidone (3× 80 mg/kg). Less potent was thiram (1× 100 mg/kg), as well as quercetin (3× 80 mg/kg), and captafol (1× 30 mg/kg). On the other hand, thiram (1× 100 mg/kg), captafol (1× 30 mg/kg), and quercetin (3× 80 mg/kg) were most potent in the CYP 2B isoenzyme induction, while furazolidone (3× 80 mg/kg), and nitrofurazone (3× 80 mg/kg) appeared to be less potent in this respect. Captan and dodine (3× 80 mg/kg) did not affect the activity of any of the cytochrome P450 isoenzymes.     

The differential effect of atrazine on luteinizing hormone release in adrenalectomized adult female Wistar rats

High doses of atrazine (ATR), administered for 4 days, suppress luteinizing hormone (LH) release and increase adrenal hormones levels. Considering the known inhibitory effects of adrenal hormones on the hypothalamo-pituitary-gonadal axis, we investigated the possible role the adrenal gland has in mediating ATR inhibition of LH release. To determine the extant and duration of adrenal activation, ovariectomized Wistar rats were given a single dose of ATR (0, 50, or 200 mg/kg), and corticosterone (CORT) levels were assayed at multiple time points posttreatment. CORT levels were increased within 20 min and remained elevated over 12 h postgavage in 200-mg/kg animals. To determine the effects of adrenalectomy on ATR inhibition of the LH surge and pulsatile LH release, adrenalectomized (ADX) or sham-operated ovariectomized rats were treated for 4 days with ATR (0, 10, 100, or 200 mg/kg), and an LH surge was induced with hormone priming. In the afternoon following the last dose of ATR, blood was sampled hourly for 9 h. Another cohort of ovariectomized rats was examined for pulsatile patterns of LH secretion after ATR (0, 50, or 200 mg/kg) and sampled every 5 min for 3 h. ADX had no effect on ATR inhibition of the LH surge but prevented the ATR disruption of pulsatile LH release. These data indicate that ATR selectively affects the LH pulse generator through alterations in adrenal hormone secretion. Adrenal activation does not play a role in ATR's suppression of the LH surge, and therefore ATR may work centrally to alter the preovulatory LH surge in female rats.     

Effect of casein diet on gonadotropin releasing hormone antagonist induced changes in adrenal gonadal functions in male rats

Adult male rats received daily injections (sc) of gonadotropin releasing hormone antagonist (0.2 mg/kg(-1) x day(-1)) for 21 days when they were sacrificed on day 22, adrenal weight, adrenal A5-3beta (delta 5-3beta) hydroxysteroid dehydrogenase (Delta5-3beta-HSD) activity and serum level of corticosterone were increased significantly while testicular 17beta (17beta) hydroxysteroid dehydrogenase (17beta-HSD) activity and serum level of testosterone and spermatogenesis were decreased in the rats fed on 5% casein diet. GnRH antagonist treated rats fed on 20% casein diet, resulted significant decrease in adrenal weight, serum corticosterone and adrenal A5-3beta-HSD activity while testicular 17beta-HSD activity serum testosterone levels and the weights of sex organs were increased with respect to anti GnRH treated rats fed on 5% casein diet. But the GnRH antagonist treated rats fed on 20% casein diet showed decreased spermatogenesis quantitatively and sperm count appeared similar to anti GnRH treated rats fed on 5% casein diet. These results indicate that high casein diet protects adrenocortical activity and stimulates testosterone synthesis without effecting spermatogenic arrest in GnRH antagonist treated rats. It may be concluded that GnRH antagonist in presence of high milk protein diet may be considered to be a suitable antihormone in the development of an ideal male contraceptive.     

Effect of Bacopa monniera and Azadirachta indica on gastric ulceration and healing in experimental NIDDM rats

Gastric ulcers were induced in normal/NIDDM rats by various physical (2 hr cold restraint stress and 4 hr pylorus ligation) and chemical agents (ethanol, 1 ml/200 g, oral, 1 hr before; aspirin, 200 mg/kg, oral, 4 hr) and duodenal ulcers were induced by cysteamine (40 mg/200 g). Ulcer healing activity was studied in gastric ulcers induced by acetic acid (50%) and HCI (0.6 M). The result indicated that in both, normal and NIDDM rats, B. monniera extract (BME, 20-100 mg/kg) did not show any significant effect on blood glucose level, while A. indica (AIE, 250-1000 mg/kg) significantly decreased it. However, both BME (50 mg/kg) and AIE (500 mg/kg) showed significant anti-ulcer and ulcer-healing activities in normal and NIDDM rats. Further, the present results also indicated that the ulcer protective effects of BME was more pronounced in non-diabetic, while that of AIE was more in NIDDM rats. The anti-ulcer and ulcer-healing activities of BME and AIE may be due to their effects on various mucosal offensive and defensive factors, and correction of blood sugar level by AIE may help to have more ulcer protective effect in NIDDM rats.     

Dietary copper deficiency alters protein levels of rat dopamine beta-monooxygenase and tyrosine monooxygenase

Perinatal copper (Cu) deficiency was studied by offering pregnant Sprague Dawley rats a basal diet low in copper, 0.44 mg/kg, and drinking water containing 0 (-Cu) or 20 (+Cu) mg Cu/L as CuSO4 starting at day 7 of gestation and continuing throughout lactation. To investigate dopamine-beta-monooxygenase (DBM) and tyrosine monooxygenase (TM) in adrenal gland and brain, offspring were weaned at Day 21 to treatments of their respective dams for 9 days. Offspring, 30 days old, of Cu-deficient (-Cu) dams were smaller, anemic, and had biochemical features characteristic of severe Cu deficiency. Adrenal DBM enzyme activity of 30-day-old -Cu rats was 40% higher than Cu-adequate (+Cu) rats and DBM protein levels, estimated by Western immunoblot, were 45% higher. Adrenal DBM mRNA levels of -Cu rats were 108% higher than +Cu rats. Adrenal TM protein levels of -Cu rats were 39% higher than +Cu rats. Hypothalamus DBM activity was significantly higher in -Cu than +Cu rats but no reproducible changes in DBM or TM protein levels could be detected by Western immunoblots. Diet history did not impact adrenal gland or hypothalamus levels of actin as detected on reblotted membranes. However, activity of the cuproenzyme Cu,Zn-superoxide dismutase was 50% lower and 30% lower, respectively, in extracts from rat adrenal gland and hypothalamus of -Cu than +Cu rats, indicating altered Cu status in the tissues studied. These data suggest that Cu deficiency is associated with increased formation of DBM and TM protein levels in adrenal gland. Further research will be required to determine the chemical signal responsible for this induction and if DBM or TM protein levels change in other tissues.     

Antinociceptive,Anti-Hyperalgesia and Antiallodynic Activities of Polyphenol Rich Extract from Shorea roxburghii against Cyclophosphamide Induced Peripheral Neuropathy

Cyclophosphamide (CYP) is a widely used antineoplastic and immunosuppressive drug, however, despite its efficacy, it has shown extensive multiple organ toxicities, including peripheral neuropathy which significantly affects the quality of life of cancer patients. This study elucidated the protective properties of Shorea roxburghii polyphenol extract (SLPE) in CYP-induced peripheral neuropathy. Rats were treated with SLPE (100 and 400 mg/kg) for five weeks plus CYP once a week from the second week of SLPE treatment. Using UHPLC-QTOF-MS, 54 polyphenolic compounds were identified in SLPE extract. After the treatment period the antinociceptive, anti-hyperalgesia and antiallodynic effects was evaluated using formalin paw edema, acetic acid abdominal writhing, hot plate, tail immersion and von Frey filament tests. While the locomotive and motor coordination effects were evaluated by open field and rotarod tests. The administration of CYP led to significant increases in mechanical and thermal hyperalgesia, in addition to hyper-nociceptive responses in the formalin and acetic acid writhing tests. CYP also significantly reduced locomotive activity and motor coordination. SLPE significantly protected against CYP-induced mechanical and thermal hyperalgesia. Furthermore, SLPE displayed robust antinociceptive effect by counteracting formalin and acetic acid induced hyper-nociception. In addition, SLPE increased the locomotive activity as well as the grip and motor coordination of the CYP treated rats. In conclusion, these results revealed the protective effects of SLPE against CYP-induced peripheral neuropathy and could be an effective therapeutic remedy for chemotherapy induced peripheral neuropathy.