Unraveling the parahormetic mechanism underlying the health-protecting effects of grapeseed procyanidins.

Proanthocyanidins (PACs), the predominant constituents within Grape Seed Extract (GSE), are intricate compounds composed of interconnected flavan-3-ol units. Renowned for their health-affirming properties, PACs offer a shield against a spectrum of inflammation associated diseases, such as diabetes, obesity, degenerations and possibly cancer. While monomeric and dimeric PACs undergo some absorption within the gastrointestinal tract, their larger oligomeric and polymeric counterparts are not bioavailable. However, higher molecular weight PACs engage with the colonic microbiota, fostering the production of bioavailable metabolites that undergo metabolic processes, culminating in the emergence of bioactive agents capable of modulating physiological processes. Within this investigation, a GSE enriched with polymeric PACs was employed to explore in detail their impact. Through comprehensive analysis, the present study unequivocally verified the gastrointestinal-mediated transformation of medium to high molecular weight polymeric PACs, thereby establishing the bioaccessibility of a principal catabolite termed 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL). Notably, our findings, encompassing cell biology, chemistry and proteomics, converge to the proposal of the notion of the capacity of VL to activate, upon oxidation to the corresponding quinone, the nuclear factor E2-related factor 2 (Nrf2) pathway-an intricate process that incites cellular defenses and mitigates stress-induced responses, such as a challenge brought by TNFα. This mechanistic paradigm seamlessly aligns with the concept of para-hormesis, ultimately orchestrating the resilience to stress and the preservation of cellular redox equilibrium and homeostasis as benchmarks of health.

Pharmacokinetic profile of bilberry anthocyanins in rats and the role of glucose transporters: LC-MS/MS and computational studies.

The aim of the present investigation was to better understand the pharmacokinetic profile of bilberry (Vaccinium Myrtillus) anthocyanins and the role of glucose transporters (sGLT1 and GLUT2) on their absorption. In particular, the absorption of 15 different anthocyanins contained in a standardized bilberry extract (Mirtoselect®) was measured in rats by a validated LC-ESI-MS/MS approach. The plasma concentration peak (Cmax) of 11.1ng/mL was reached after 30min and fasting condition significantly increased the bioavailability of anthocyanins by more than 7 fold in respect to fed rats. Glucose co-administration did not interfere with the overall anthocyanin uptake. Bioavailability of each anthocyanin was then estimated by comparing the relative content in plasma vs extract. The 15 anthocyanins behaved differently in term of bioavailability and both the aglycone and the sugar moiety were found to affect the absorption. For instance, arabinoside moiety was detrimental while cyanidin enhanced bioavailability. Computational studies permitted to rationalize such results, highlighting the role of glucose transporters (sGLT1 and GLUT2) in anthocyanins absorption. In particular a significant correlation was found for the 15 anthocyanins between sGLT1 and GLUT2 recognition and absorption.

A Systematic Review on the Effects of Botanicals on Skeletal Muscle Health in Order to Prevent Sarcopenia.

We performed a systematic review to evaluate the evidence-based medicine regarding the main botanical extracts and their nutraceutical compounds correlated to skeletal muscle health in order to identify novel strategies that effectively attenuate skeletal muscle loss and enhance muscle function and to improve the quality of life of older subjects. This review contains all eligible studies from 2010 to 2015 and included 57 publications. We focused our attention on effects of botanical extracts on growth and health of muscle and divided these effects into five categories: anti-inflammation, muscle damage prevention, antifatigue, muscle atrophy prevention, and muscle regeneration and differentiation.

The effect of ginger (Zingiber officinalis) and artichoke (Cynara cardunculus) extract supplementation on gastric motility: a pilot randomized study in healthy volunteers.

OBJECTIVE: Prodigest® is the standardized combination of artichoke and ginger extracts. This combination was safe and effective in the treatment of functional dyspepsia. However, further evidence could be useful to shed new lights on the effect of Prodigest® on gastric motility. This pilot randomized study on healthy volunteers investigates the prokinetic activity of Prodigest®. SUBJECTS AND METHODS: This was a randomized, cross-over study in healthy volunteers comparing Prodigest® versus placebo. Eleven healthy volunteers were enrolled. Each participant underwent two evaluations, at a 7-day interval. Ten minutes before the main meal, the baseline area of gastric volume was determined by ultrasonography. The subject was then given one Prodigest® or placebo capsule and, then consumed a standardized meal. One hour after the meal, the gastric volume was measured again. Two weeks after the second evaluation, three subjects repeated the above-mentioned procedures taking two capsules of Prodigest®. RESULTS: The mean gastric area at baseline was 3.2 ± 0.5 cm(2); after the meal, this figure was 8.4 ± 0.7 cm(2) with Prodigest® and 11.0 ± 1.5 cm2 with placebo (p<0.001). The after-meal gastric area was significantly smaller, with a -24% difference, following the combination of extracts, as compared with placebo (p<0.001). The effect of two capsules of Prodigest® seems to be more evident but due to the very small number of the patients sample further clinical data are necessary before confirming the dose-related effects. CONCLUSIONS: This pilot study shows that Prodigest®, a standardized extract of ginger and artichoke, significantly promotes gastric emptying in healthy volunteers without being associated with notable adverse effects.

Can nausea and vomiting be treated with ginger extract?

Ginger (Zingiber officinale) is a spice traditionally used to treat indigestion, nausea and vomiting. Ginger extracts accelerate gastric emptying and stimulate gastric antral contractions. These effects are mainly due to the presence of gingerols and shogaols and their activity on cholinergic M receptors and serotonergic 5-HT and 5-HT receptors. Various researches on this subject have led to controversial results, due to the chemical instability of ginger extracts and particularly of gingerols, which are readily-oxidizable substances. A systematic review of double-blind, placebo-controlled, randomized studies highlighted the potential efficacy of ginger on the prevention and treatment of nausea and vomiting of various origins, even though additional controlled studies are needed. This review focuses on pregnancy-induced nausea and vomiting and on chemotherapy induced nausea, and hypothesizes a therapeutic role for ginger extracts in case of side effects, as an alternative to traditional prokinetic drugs such as domperidone, levosulpiride or metoclopramide.

Cranberry supplementation in the prevention of non-severe lower urinary tract infections: a pilot study.

OBJECTIVE: Cranberry extracts have been tested as a nutritional supplementation in the prevention of recurrent lower-urinary tract infections (R-UTIs), with mixed results. This pilot, registry study evaluates the prophylactic effects of oral supplementation with a new well-standardized cranberry extract in patients with R-UTI, over a 2-month follow-up. PATIENTS AND METHODS: All subjects were suggested to take one capsule containing a cranberry extract (Anthocran™) for 60 days and were also given lifestyle advice. Clinical outcomes were compared between patients on cranberry extracts and those who don't take this supplementation. RESULTS: In total, 22 subjects completed the study in each of the two groups. In the cranberry group, the reduction in the frequency of UTI episodes during the study period compared with the two months before the inclusion was 73.3% (p < 0.05). This figure was 15.4% in the control group (p < 0.05; p = 0.012 vs cranberry group). Seven (31.8%) subjects in the cranberry group were symptom-free; no patient was symptom-free in the control group (p < 0.05). The mean duration of UTI episodes was 2.5 ± 1.3 days in the cranberry group, compared with 3.6 ± 1.7 days in subjects not on cranberry (p < 0.05). Three subjects (13.6%) in the cranberry group and 8 (36.3%) in the control group required medical consultation for UTI symptoms (p < 0.05). Urine evaluation was completely negative in 20/22 subjects in the Cranberry group (90.9%) and in 11 control subjects (50.0%; p < 0.005). No adverse events were observed. CONCLUSIONS: These preliminary results, obtained in a field-practice setting, indicates the effectiveness and safety of a well-standardized cranberry extract in the prevention of R-UTI.

SAMITAL® improves chemo/radiotherapy-induced oral mucositis in patients with head and neck cancer: results of a randomized, placebo-controlled, single-blind Phase II study.

PURPOSE: This randomised, placebo-controlled single-blind trial investigated the safety and efficacy of SAMITAL®, a formulation of highly standardised botanical extracts, in the treatment of chemo/radiotherapy-induced oral mucositis (OM) in patients with head and neck cancer. METHODS: Patients received SAMITAL® or placebo four times daily for up to 50 days during scheduled chemo/radiotherapy. Severity of OM was monitored according to a modified WHO severity scale, and pain and quality-of-life assessments were based on the effect of symptoms of OM on relevant daily activities, according to a visual analogue scale. RESULTS: Mean scores for the severity of OM were significantly (p < 0.05 versus baseline) reduced from day 31 until the end of treatment in patients treated with SAMITAL® (n = 20). No significant improvement was observed in the placebo group (n = 10). Pain reduction was significant from day 4 till end of treatment with SAMITAL® and from days 7 to 21 in placebo patients. SAMITAL® also significantly improved quality of life, as shown by improvements in scores for relevant daily activities including eating, drinking and sleeping. All SAMITAL® patients completed the treatment period, but no placebo recipients completed treatment. No severe adverse events were observed with SAMITAL®, and systemic absorption of relevant active ingredients was undetectable. CONCLUSIONS: SAMITAL® significantly decreased the severity of chemo/radiotherapy-induced OM in patients with head and neck cancer, with no treatment-related adverse events. Pain relief lasted through the treatment period, and improvements in quality of life were reflected by the significant benefits of SAMITAL® on activities like drinking, eating and speaking.

Bacterial biofilm formation inhibitory activity revealed for plant derived natural compounds.

Use of herbal plant remedies to treat infectious diseases is a common practice in many countries in traditional and alternative medicine. However to date there are only few antimicrobial agents derived from botanics. Based on microbiological screening tests of crude plant extracts we identified four compounds derived from Krameria, Aesculus hippocastanum and Chelidonium majus that showed a potentially interesting antimicrobial activity. In this work we present an in depth characterization of the inhibition activity of these pure compounds on the formation of biofilm of Staphylococcus aureus as well as of Staphylococcus epidermidis strains. We show that two of these compounds possess interesting potential to become active principles of new drugs.

A randomized, double-blind, placebo-controlled trial to evaluate efficacy and tolerability of an optimized botanical combination in the management of patients with primary hypercholesterolemia and mixed dyslipidemia.

This study compared the efficacy and tolerability of an optimized botanical combination containing policosanol, tomato extract, orally bioavailable grape procyanidins and Oenothera biennis oil against placebo in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. Such a combination is endowed with biological properties targeted to cholesterol control and vasoprotection. This randomized, double-blind, parallel-group trial consisted of a 6 week treatment period following 4 week baseline period, and a 2 week post-treatment follow-up. At baseline, both the groups were comparable to each other. Both the active treatment and the placebo group included 30 patients (active treatment: mean age 46.80 ± 7.43 years, nine males; placebo: mean age 45.50 ± 6.76 years, eight males). Significant reductions in the LDL-cholesterol (LDL-C; -17.33% from baseline, p < 0.001) and total cholesterol (TC; -13.38% from baseline, p < 0.0001) values over the treatment period were observed with the tested product. The treatment also resulted in reductions in C-reactive protein (CRP), malondialdehyde (MDA) and superoxide dismutase (SOD) values, which are indices of oxidative stress. This rational combination of different compounds is effective and safe in lowering the elevated LDL-C and TC values. It is also effective in the modulation of the oxidation indices values; however, a further long term study in a larger population would be needed in order to confirm these preliminary findings.

The hyperforin derivative IDN5706 occludes spatial memory impairments and neuropathological changes in a double transgenic Alzheimer's mouse model.

The use of natural compounds is an interesting stratagem in the search of drugs with therapeutic potential for the treatment of Alzheimer's disease (AD). We report here the effect of the hyperforin derivative (IDN5706, tetrahydrohyperforin), a semi-synthetic derivative of the St. John's Wort, on the brain neuropathology, learning and memory in a double transgenic (APPswe, PS-1dE9) mouse model of AD. Results indicate that, IDN5706 alleviates memory decline induced by amyloid-beta (Abeta) deposits as indicated by the Morris water maze paradigm. Moreover, the analysis of Abeta deposits by immunodetection and thioflavin-S staining of brain sections, only reveals a decrease in the frequency of the larger-size Abeta deposits, suggesting that IDN5706 affected the turnover of amyloid plaques. Immunohistochemical analysis, using GFAP and n-Tyrosine indicated that the hyperforin derivative prevents the inflammatory astrocytic reaction and the oxidative damage triggered by high Abeta deposit levels. We conclude that the hyperforin derivative, IDN5706, has therapeutic potential for prevention and treatment of AD.

Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3-i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III), a new oral c-seco-taxane derivative with antiangiogenic property effective on paclitaxel-resistant tumors.

IDN 5390 (13-(N-Boc-3-i-butylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III) is a new taxane, derived from 7,8-C-seco-10-deacetylbaccatin, selected for its ability to inhibit angiogenesis, mainly by acting on endothelial cell motility, and for its selective activity on class III beta-tubulin. In vivo, IDN 5390 shows activity against paclitaxel-sensitive and -resistant tumors when administered on a prolonged, continuous dosage schedule. We studied the pharmacokinetics and bioavailabilty of the drug in mice after single and repeated oral treatment. IDN 5390 was rapidly absorbed after oral administration, with good bioavailability (43%). After intravenous injection, it was extensively distributed in tissue, mainly the liver, kidney, and heart, with low but persistent levels in brain. The kinetics appear dose-dependent with a clearance of 2.6, 1.4, and 0.9 l/kg at, respectively, 60, 90, and 120 mg/kg, and a half-life 24, 36, and 54 min. After prolonged daily oral doses given for 2 weeks, we found that there was a decrease in drug availability; i.e., the area under the concentration-time curve value after p.o. daily administration on day 14 was 2-fold lower than that on day 1. Metabolism plays a major role in elimination of the drug, and at least 12 metabolites were identified in feces and urine. The percentage excreted as metabolites after an oral dose (42%) was higher than that after the i.v. dose (33%), suggesting a first-pass effect. Four metabolites were found in plasma at detectable levels; one of them, with restored taxane scaffold, is a species 3 times more potent than IDN 5390, possibly contributing to the observed anti-tumor activity.

Antioxidant activity of polyphenols from solid olive residues of c.v. Coratina.

The antioxidant profile of extracts from solid olive residue (SOR) of c.v. Coratina, a cultivar widely diffused in the south of Italy, using both cell-free and cell-based experimental models, was investigated. A total hydroalcoholic extract (polyphenols content 19.7%) and a purified extract (Oleaselecttrade mark) (polyphenols content 35.1%) were tested for their ability to quench the stable free radical DPPH, the peroxyl radicals (ORAC assay), by monitoring the loss in fluorescence of R-phycoerythrin induced by the peroxyl radical generator AAPH and their ability to inhibit the cumene hydroperoxide-induced lysis of rat red blood cells (RBC). The total hydroalcoholic extract showed IC(50) 26.96+/-1.53 microg/ml in the DPPH assay, that 10 microg/ml were equivalent to 2.11+/-0.12 microg/ml Trolox (ORAC assay) and IC(50) 1.7+/-0.20 microg/ml in the RBC hemolysis. The Oleaselect extract was 4 to 5 folds more active than the hydroalcoholic extract in all the experimental models, with IC(50) values of 7.36+/-0.38 microg/ml in the DPPH test and of 0.38+/-0.03 microg/ml in RBC; the antioxidant activity in the ORAC assay was slightly greater than that of Trolox (10 microg/ml equivalent to 11.45+/-0.40 microg/ml). The scavenging effect of the extract in the ORAC assay was compared to that of verbascoside (the main polyphenol component) and of caffeic acid (the basic constituent of verbascoside): the results indicate that caffeic acid (10 microg/ml equivalent to 35.70+/-2.95 microg/ml Trolox) is more potent than verbascoside (10 microg/ml equivalent to 15.42+/-1.21 microg/ml Trolox) in entrapping peroxyl radicals. Finally the antioxidant activity of the Oleaselect extract was confirmed in human umbilical endothelial cells (EC) exposed to the site-specific peroxyl radical inducer AAPH, where a massive lipid peroxidation process (marker the fluorescence probe BODIPY) takes place, paralleled by a marked loss of cell viability (calcein assay). The purified extract (1-20 microg/ml) pre-incubated with EC for 1 h dose-dependently inhibited both the lipid-peroxidation damage and cell death. Taking into account the total polyphenol content, these results clearly indicate a greater antioxidant activity for the purified extract, due to a cooperative antioxidant interaction among its polyphenol constituents.

Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine.

Tanacetum parthenium (TP) is a member of the Asteracee family long used empirically as a herbal remedy for migraine. So far, however, clinical trials have failed to prove consistently the effectiveness of TP extracts in preventing migraine attacks, probably as a consequence of the uncertainty as regards the active principle. In this study, the biological effects of different TP extracts and purified parthenolide were tested in an animal model of migraine based on the quantification of neuronal activation induced by nitroglycerin. The extract enriched in parthenolide significantly reduced nitroglycerin-induced Fos expression in the nucleus trigeminalis caudalis. Purified parthenolide inhibited nitroglycerin-induced neuronal activation in additional brain nuclei and, significantly, the activity of nuclear factor-kappaB. These findings strongly suggest that parthenolide is the component responsible for the biological activity of TP as regards its antimigraine effect and provide important information for future controlled clinical trials.

In vitro and in vivo immune stimulating effects of a new standardized Echinacea angustifolia root extract (Polinacea).

Polinacea is a new standardized hydroethanolic extract obtained from Echinacea angustifolia roots containing echinacoside (>4%), the high molecular weight polysaccharide IDN 5405 (>5%) and a isobutylamide fraction (<0.1%). For in vitro tests, a bacterial lipopolysaccharide-free (LPS-free) Polinacea has been prepared in order to avoid non-specific responses of immunocompetent cells. LPS-free Polinacea enhanced the immune functions as highlighted by the proliferation rate and gamma-interferon production in murine T-lymphocyte cell cultures stimulated by anti-CD3. LPS-free Polinacea did not have a direct role on macrophage response as measured in the nitric oxide production test using the J774 macrophage cells line. In vivo, Polinacea showed an immune stimulating activity by reducing the Candida albicans induced mortality both in normal and in cyclosporin A-treated mice.

High-performance liquid chromatography measurement of hyperforin and its reduced derivatives in rodent plasma.

A reverse-phase high-performance liquid chromatography method was developed for the determination of hyperforin and its reduced derivatives octahydrohyperforin and tetrahydrohyperforin in rodent plasma. The procedure includes solid-phase extraction from plasma using the Baker 3cc C8 cartridge, resolution on the Symmetry Shield RP8 column (150 mm x 4.6 mm, i.d. 3.5 microm) and UV absorbance detection at 300 nm. The assay was linear over a wide range, with an overall coefficient of variation less than 10% for all compounds. The precision and accuracy were within acceptable limits and the limit of quantitation was sufficient for studies preliminarily assessing the disposition of tetrahydrohyperforin and octahydrohyperforin in the mouse and rat.

Molecular biology and the staging of prostate cancer.

Cancer of the prostate is still controlled or cured by surgery, radiotherapy, and hormone therapy. The present criteria of complication and prediction are criticized more and more for not being sufficiently reliable, due to the high heterogeneity of prostatic cells. The continuing discoveries of intra- and extracellular mechanisms of the molecular informational network, which allow the continuity or discontinuity of the cell's life, are also related to prostate cancer. The role of androgen receptors is now under close scrutiny, in the light of the knowledge of regulatory genes and their molecular expression. In the near future, a complete study of prostate cancer's DNA is certainly envisaged. Looking forward to the extraordinary applications of molecular biology in this field, this article is aimed at establishing a clear link between the conventional ways of interpreting the clinical expression of prostate cancer and the oncoming applications of genomics and proteomics.

Antitumour activity of the silybin-phosphatidylcholine complex, IdB 1016, against human ovarian cancer.

This study aimed to assess, in an in vivo experimental model, the growth inhibitory effects of IdB 1016 (Silipide, a complex of silybin/phosphatidylcholine) when used as a single agent against human ovarian cancer. We also wanted to investigate the mechanism of the antiangiogenic action by assessing Vascular Endothelial Growth Factor (VEGF) levels and by using macroarray technology to evaluate the regulation of a panel of genes involved in angiogenesis. We also aimed to establish the plasma and tumour bioavailability of silybin after repeated administration of IdB 1016. Female nude mice bearing human ovarian cancer xenografts (A2780) received 450 mg/kg/day IdB 1016 daily by oral gavage until the end of the study. At sacrifice, blood and tumour specimens were collected and subsequently processed for the determination of silybin levels, VEGF levels or a gene expression profile. IdB 1016 was significantly active in inhibiting ovarian tumour growth. Treatment with 450 mg/kg/day for a total of 20 administrations produced a tumour weight inhibition (TWI%) of 78% and a Log10 Cell Kill (LCK) of 1.1. Free silybin levels were found to be 7.0+/-5.3 microg/ml and 183.5+/-85.9 ng/g tissue (mean+/-standard deviation (S.D.)) in the plasma and tumour samples, respectively. No significant differences were found in the concentration of human VEGF in xenografts from control and IdB 1016-treated mice. The array analysis suggested the downregulation of the VEGR receptor 3 and the upregulation of angiopoietin-2 as potential mechanisms for the antiangiogenic activity. In conclusion, these findings suggest IdB 1016 is a good candidate, with a relevant clinical potential, for use in the management of recurrent ovarian cancer. A phase II, non-randomised clinical study is now ongoing in our Institute aimed at evaluating the efficacy of daily administrations of IdB 1016 in the serological recurrence of ovarian cancer.

IDN 5390: an oral taxane candidate for protracted treatment schedules.

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always >85%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg(-1). In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD=10 mg kg(-1)). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

High-performance liquid chromatographic assay for the determination of the novel C-Seco-taxane derivative (IDN 5390) in mouse plasma.

A HPLC assay was developed to determine IDN 5390, a new paclitaxel analogue, in mouse plasma. The method involves solid-phase extraction from cyano cartridges (recovery >80%), HPLC separation on Symmetry C(18) (4.6 x 150 mm), on isocratic mobile phase of water-acetonitrile-acetic acid (49:50:1) and detection at 227 nm. Retention times of IDN 5390 and IDN 5517 (internal standard, I.S.) were 9.1 and 10.5 min, respectively. The assay was linear from 0.05 to 5 micro g/ml (r(2)>or=0.995), showed intra- and inter-day precision within 1.0 and 6.2%, and accuracy of 94.7-106.8%. LOQ was 0.050 micro g/ml. Using this method IDN 5390 pharmacokinetics was determined in mice.

A study of the antidepressant activity of Hypericum perforatum on animal models.

The treatment of non-selected depressed patients with a hydro-alcoholic extract of Hypericum perforatum has been reported to have an efficacy similar to that of classical antidepressants. The effects of H. perforatum on three animal depression models have been studied: (a) an acute form of escape deficit (ED) induced by unavoidable stress; (b) a chronic model of ED, which can be maintained by the administration of mild stressors on alternate days; (c) a model of anhedonia based on the finding that repeated stressors prevent the development of appetitive behavior induced by vanilla sugar in satiated rats fed ad libitum. H. perforatum: (i) acutely protects animals from the sequelae of unavoidable stress; (ii) reverts the chronic escape deficit state maintained by repeated stressors and (iii) preserves the animal's capacity to acquire motivated appetitive behavior. Exposure to chronic stress not only induces escape deficit, but also decreases extraneuronal levels of dopamine in the nucleus accumbens shell; both behavioral and neurochemical effects are reverted by long-term treatment with antidepressants. Three-week treatment with H. perforatum reverted the chronic stress effect on extraneuronal dopamine in the nucleus accumbens. A consistent body of data in the literature suggests that, among the components of H. perforatum extract, hyperforin is the compound (or one of the compounds) responsible for the antidepressant activity. We compared the efficacy of the total extract with the efficacy of hyperforin after p.o. administration. In the acute-escape deficit model, hyperforin showed a potency of about ten times that of the total extract in protecting rats from the sequelae of unavoidable stress. Thus, hyperforin appears to be the most likely active component responsible for the antidepressant activity of H. perforatum.