hyperforin and Disease-Models--Animal

Hypericum perforatum (Hp) extracts contain many different classes of constituents including flavonoids and biflavonoids, phloroglucinols, naphthodianthrones, caffeic acid derivatives, and unknown and/or unidentified compounds. Many constituents may be responsible for the anti-inflammatory activity of Hp including quercetin and derivatives, hyperforin, pseudohypericin, and amentoflavone. In line with antidepressant data, it appears that the interactions of constituents may be important for the anti-inflammatory activity of Hp. Interactions of constituents, tested in bioavailability models, may explain why synergistic mechanisms have been found to be important for antidepressant and antiproliferative bioactivities. This review highlights the relationship among individual constituents and the anti-inflammatory activity of Hp extracts and proposes that interactions of constituents may be important for the anti-inflammatory activity of botanical extracts, although the exact mechanisms of the interactions are still unclear.

Topics: Animals; Anti-Inflammatory Agents; Biflavonoids; Disease Models, Animal; Flavonoids; Humans; Hypericum; Perylene; Phloroglucinol; Plant Extracts; Signal Transduction; Terpenes

St. John's wort (Hypericum perforatum L., SJW) contains numerous compounds with documented biological activity. Constituents that have stimulated the most interest include the naphthodianthrones hypericin and pseudohypericin, a broad range of flavonoids, and the phloroglucinols hyperforin and adhyperforin. According to the actual state of scientific knowledge the total extract has to be considered as the active substance. Although there are some open questions, the bulk of data suggests that several groups of active compounds are contributing to the antidepressant efficacy of the plant extract.

Topics: Animals; Anthracenes; Antidepressive Agents; Bridged Bicyclo Compounds; Cells, Cultured; Clinical Trials as Topic; Disease Models, Animal; Humans; Hypericum; Ice; Meta-Analysis as Topic; Perylene; Phloroglucinol; Phytotherapy; Plant Extracts; Terpenes

Clinical data indicate that hydroalcoholic extracts of Hypericum perforatum might be as valuable as conventional antidepressants in mild-to-moderate depression, with fewer side effects. One clinical trial using two extracts with different hyperforin contents indicated it as the main active principle responsible for the antidepressant activity. Behavioural models in rodents confirm the antidepressant-like effect of Hypericum extracts and also of pure hyperforin and hypericin. A hydroalcoholic extract lacking hyperforin also lacks the antidepressant-like effect. According to pharmacokinetic data and binding studies, it appears that the antidepressant effect of Hypericum extract is unlikely be due to an interaction of hypericin with central neurotransmitter receptors. The main in vitro effects of hyperforin (at concentrations of 0.1-1 microM) are non-specific presynaptic effects, resulting in the non-selective inhibition of the uptake of many neurotransmitters, and the interaction with dopamine D1 and opioid receptors. However, it is still not clear whether these mechanisms can be activated in vivo, since after administration of Hypericum extract brain concentrations of hyperforin are well below those active in vitro. In the rat, Hypericum extract might indirectly activate sigma receptors in vivo (through the formation of an unknown metabolite or production of an endogenous ligand), suggesting a new target for its antidepressant effects.

Topics: Animals; Anthracenes; Bridged Bicyclo Compounds; Depression; Disease Models, Animal; Hypericum; Neurotransmitter Agents; Perylene; Phloroglucinol; Phytotherapy; Plant Extracts; Rats; Receptors, Dopamine D1; Receptors, Opioid; Terpenes

The phloroglucinol derivative hyperforin has been recently shown to be a major antidepressant component in the extract of Hypericum perforatum. Experimental studies clearly demonstrated its activity in different behavioral models of depression. Moreover clinical studies linked the therapeutic efficacy of Hypericum extracts to their hyperforin content, in a dose-dependent manner. The molecular mechanism of action of hyperforin is still under investigation. Hyperforin has been shown to inhibit, like conventional antidepressants, the neuronal uptake of serotonin, norepinephrine and dopamine. However, hyperforin inhibits also the uptake of gamma-aminobutyric acid (GABA) and L-glutamate. The uptake inhibition by hyperforin does not involve specific binding sites at the transporter molecules; its mechanism of action seems to be related to sodium conductive pathways, leading to an elevation in intracellular Na(+) concentration. Other additional mechanisms of action of hyperforin, involving ionic conductances as well synaptosomal and vesicular function, have been suggested. In addition to its antidepressant activity, hyperforin has many other pharmacological effects in vivo (anxiolytic-like, cognition-enhancing effects) and in vitro (antioxidant, anticyclooxygenase-1, and anticarcinogenic effects). These effects could be of clinical importance. On the other hand, the role of hyperforin in the pharmacological interactions occurring during Hypericum extract therapy must be fully investigated. Hyperforin seems to be responsible for the induction of liver cytochrome oxidase enzymes and intestinal P-glycoprotein. Several pharmacokinetic studies performed in rats and humans demonstrated oral bioavailability of hyperforin from Hypericum extract. Only recently a new chromatographic method for detection of hyperforin in the brain tissue has been developed and validated. Taking into account the chemical instability of hyperforin, current efforts are directed to the synthesis of new neuroactive derivatives.

Topics: Animals; Antidepressive Agents; Bridged Bicyclo Compounds; Clinical Trials as Topic; Depression; Disease Models, Animal; Drug Interactions; Humans; Hypericum; Phloroglucinol; Terpenes

Photodynamic therapy with hypericin (HY-PDT) and hyperforin (HP) could be treatment modalities for colorectal cancer (CRC), but evidence of their effect on angiogenic factors in CRC is missing. Convenient experimental model utilization is essential for angiogenesis research. Therefore, not only 2D cell models, but also 3D cell models and micro-tumors were used and compared. The micro-tumor extent and interconnection with the chorioallantoic membrane (CAM) was determined by histological analyses. The presence of proliferating cells and HY penetration into the tumor mass were detected by fluorescence microscopy. The metabolic activity status was assessed by an colorimetric assay for assessing cell metabolic activity (MTT assay) and HY accumulation was determined by flow cytometry. Pro-angiogenic factor expression was determined by Western blot and quantitative real-time polymerase chain reaction (RT-qPCR). We confirmed the cytotoxic effect of HY-PDT and HP and showed that their effect is influenced by structural characteristics of the experimental model. We have pioneered a method for analyzing the effect of HP and cellular targeted HY-PDT on pro-angiogenic factor expression in CRC micro-tumors. Despite the inhibitory effect of HY-PDT and HP on CRC, the increased expression of some pro-angiogenic factors was observed. We also showed that CRC experimental micro-tumors created on quail CAM could be utilized for analyses of gene and protein expression.

Topics: Angiogenesis Inducing Agents; Animals; Anthracenes; Biomarkers; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Colorectal Neoplasms; Disease Models, Animal; Gene Expression; Humans; Neovascularization, Pathologic; Perylene; Phloroglucinol; Photochemotherapy; Photosensitizing Agents; Terpenes

Hyperforin, a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), has been shown to be neuroprotective against acute ischemic stroke. However, the underlying mechanisms are still unclear and need to be fully elucidated. C57BL/6 wildtype (WT) mice or interleukin (IL)-17A knock-out mice were subjected to middle cerebral artery occlusion (60min) followed by reperfusion for 72h. Hyperforin (0.5μg) was injected slowly into the right ventricle of WT mice 1, 24 and 48h after middle cerebral artery occlusion (MCAO) onset. Here, we found that hyperforin treatment decreased the mRNA and protein expression of IL-17A at 72h after MCAO onset. Hyperforin reduced infarct volumes and increased neurologic scores accompanied by a decrease in microglial activation and a shift from M1 to M2 phenotypes in the peri-infarct striatum. Furthermore, we revealed that IL-17A was essential to the microglial activation in the acute phase of ischemic stroke. IL-17A knock-out (il-17a

Topics: Animals; Brain Infarction; Brain Injuries; Cytokines; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Intercellular Signaling Peptides and Proteins; Interleukin-17; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neuroprotective Agents; Phloroglucinol; Proprioception; Statistics, Nonparametric; Terpenes

The current investigation aimed to scrutinize the neuro-protective effect of hyperforin on β‑amyloid peptide (Aβ)

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Colchicine; Disease Models, Animal; Dose-Response Relationship, Drug; L-Lactate Dehydrogenase; Male; Malondialdehyde; Neuroprotective Agents; NF-kappa B; Oxidative Stress; PC12 Cells; Peptide Fragments; Phloroglucinol; Rats; Rats, Wistar; Signal Transduction; Terpenes

To investigate the effect of the hyperforin (HF) on learning and memory function and Aβ₁₋₄₂, βAPP and BACE1 protein expressions in hippocampus of five-month-old APP/PS1 double transgenic mice, and discuss the underlying mechanism of HF. The five-month-old APP/PS1 double transgenic mice were randomly divided into the model group, rosiglitazone group (12 mg•kg⁻¹•d⁻¹) and HF high dose, middle dose and low dose groups (600, 300 and 150 mg•kg⁻¹•d⁻¹) in each group; in addition, 15C57BL/6J mice with the same months and background were selected as normal group. Drugs were diluted in the same volume before using, and then administrated by ig for 7 months, 1 time a day; the mice in normal group and model group received the same volume of distilled water. The learning and memory ability was tested by Morris water maze; Aβ₁₋₄₂, βAPP and BACE1proteinexpressionlevelswere tested by immunohistochemistry and Western blot. The Morris water maze results showed that as compared with the normal group, the learning and memory ability was significantly impaired in mice of model group (P<0.01); as compared with the model group, the learning and memory ability was improved in mice of rosiglitazone group and HF high, middle and low dose groups(P<0.01 or P<0.05). Immunohistochemistry and western blot results showed thatas compared with the normal group, the Aβ₁₋₄₂, βAPP and BACE1 protein expression levels in hippocampus were significantly increased in mice of model group (P<0.01);as compared with the model group, Aβ₁₋₄₂, βAPP and BACE1 protein expression levels in hippocampus were decreased in mice of rosiglitazone group and HF high, middle and low dose groups (P<0.01 or P<0.05). HF may improve the learning and memory ability of AD model mice via inhibition of βAPP and BACE1 protein expressions, thus reduced the generation of Aβ₁₋₄₂ proteins and amyloid plaque deposits in the brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Mice, Transgenic; Peptide Fragments; Phloroglucinol; Terpenes

Multiple sclerosis (MS) is a central nervous system disorder mainly characterized by inflammation, demyelination and axonal injury. Anti-inflammatory agents can be used to ameliorate the disease process. Hypericum perforatum L or St. John's wort is widely used as an anti-depressant and anti-inflammatory remedy in traditional and herbal medicine. Based on St. John's wort properties, the therapeutic potentials of an H. perforatum extract (HPE) and a single component, hyperforin were evaluated for effectiveness against MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. Female C57BL/6 mice were immunized with specific antigen MOG35-55 and then administered different doses of hyperforin or HPE post-immunization. Clinical symptoms/other relevant parameters were assessed daily. Histological analysis of the spinal cord was performed. T-cell proliferative activity was also evaluated using a BrdU assay. The effect of hyperforin on regulatory T-cells (Treg cells) was assessed using flow cytometry. The results indicate hyperforin and HPE reduced the incidence and severity of EAE, an outcome that closely correlated with an inhibition of pathological features (leukocyte infiltration and demyelination) and antigen-specific T-cell proliferation. The study also showed that hyperforin caused increased Treg cell levels in the spleen. These results indicated that hyperforin and HPE could attenuate EAE autoimmune responses by inhibiting immune cell infiltration and expansion of Treg cell and could eventually be considered as a potential candidate for use in the treatment of MS.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Hypericum; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Phloroglucinol; Phytotherapy; Spleen; T-Lymphocytes, Regulatory; Terpenes

An increasing number of researches have focused on the cognitive changes in depression patients. Here, we observed impaired cognitive ability in a rat depression model along with down-regulated expression of canonical transient receptor potential 6 (TRPC6) protein. The cognitive defect could be rescued by treatment with hyperforin, which can invoke TRPC6 activation. This study was designed as following: rats were randomly divided into control, stressed and stressed+hyperforin groups. Chronic unpredictable stress combined with isolation rearing was applied on rats for three weeks, except for control group. Morris water maze was applied to evaluate spatial cognitive ability while long-term potentiation (LTP) was recorded to test the synaptic plasticity. Results showed that both spatial cognition and synaptic plasticity were impaired in stress group while improved after hyperforin treatment in stressed+hyperforin group, meanwhile, Western blot assay showed that TRPC6 expression was decreased in stressed group. The histological data also presented the decline of dendritic length, dendritic spine density and the number of excitatory synapses in stress group while they were increased in stressed+hyperforin group. These results suggest that there is a well potential of TRPC6 to become a new target for selecting promising new candidates as antidepressants with therapeutically effect on impaired cognition.

Topics: Animals; Body Weight; Central Nervous System Agents; Cognition; Cognition Disorders; Dendrites; Depressive Disorder; Dietary Sucrose; Disease Models, Animal; Down-Regulation; Feeding Behavior; Long-Term Potentiation; Male; Maze Learning; Phloroglucinol; Rats, Wistar; Reversal Learning; Social Isolation; Stress, Psychological; Terpenes; TRPC Cation Channels; Uncertainty

Tetrahydrohyperforin (IDN-5706) is a semisynthetic derivative of hyperforin, one of the main active components of Hypericum perforatum extracts. It showed remarkable positive effects on memory and cognitive performances in wild-type mice and in a transgenic mouse model of Alzheimer's disease, but little was known about the concentrations it can reach in the brain. The investigations reported herein show that repeated treatment of mice with tetrahydrohyperforin (20 mg/kg intraperitoneally, twice daily for 4 days and once on the fifth day) results in measurable concentrations in the brain, up to 367 ng/g brain (∼700 nM) 6 h after the last dose; these concentrations have significant effects on synaptic function in hippocampal slices. The other main finding was the identification and semiquantitative analysis of tetrahydrohyperforin metabolites. In plasma, three hydroxylated/dehydrogenated metabolites were the largest (M1-3) and were also formed in vitro on incubation of tetrahydrohyperforin with mouse liver microsomes; the fourth metabolite in abundance was a hydroxylated/deisopropylated derivative (M13), which was not predicted in vitro. These metabolites were all detected in the brain, with peak areas from 10% (M1) to ∼1.5% (M2, M3, and M13) of the parent compound. In summary, repeated treatment of mice with tetrahydrohyperforin gave brain concentrations that might well underlie its central pharmacological effects. We also provide the first metabolic profile of this compound.

Topics: Alzheimer Disease; Animals; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Hippocampus; Hypericum; Mice; Microsomes, Liver; Molecular Structure; Phloroglucinol; Terpenes

The adenosine triphosphate-binding cassette transport protein P-glycoprotein (ABCB1) is involved in the export of beta-amyloid from the brain into the blood, and there is evidence that age-associated deficits in cerebral P-glycoprotein content may be involved in Alzheimer's disease pathogenesis. P-glycoprotein function and expression can be pharmacologically induced by a variety of compounds including extracts of Hypericum perforatum (St. John's Wort). To clarify the effect of St. John's Wort on the accumulation of beta-amyloid and P-glycoprotein expression in the brain, St. John's Wort extract (final hyperforin concentration 5%) was fed to 30-day-old male C57BL/6J-APP/PS1(+/-) mice over a period of 60 or 120 days, respectively. Age-matched male C57BL/6J-APP/PS1(+/-) mice receiving a St. John's Wort-free diet served as controls. Mice receiving St. John's Wort extract showed (i) significant reductions of parenchymal beta-amyloid 1-40 and 1-42 accumulation; and (ii) moderate, but statistically significant increases in cerebrovascular P-glycoprotein expression. Thus, the induction of cerebrovascular P-glycoprotein may be a novel therapeutic strategy to protect the brain from beta-amyloid accumulation, and thereby impede the progression of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Disease Models, Animal; Hypericum; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phloroglucinol; Plant Extracts; Terpenes

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aβ assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aβ accumulation in AD mouse models. In the present study, we examined the effects of THH on Aβ-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young AβPPSwe/PSEN1ΔE9 (AβPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AβPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aβ-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD.

Topics: Aldehydes; Alzheimer Disease; Animals; Brain; Caspase 3; Disease Models, Animal; Enzyme Activation; Hippocampus; Male; Maze Learning; Memory; Mice; Mice, Transgenic; Phloroglucinol; Plaque, Amyloid; Receptors, Nicotinic; Terpenes

Soluble β-amyloid peptides (Aβ) and small Aβ oligomers represent the most toxic peptide moieties recognized in brains affected by Alzheimer's disease (AD). Here we provide the first evidence that specific St. John's wort (SJW) extracts both attenuate Aβ-induced histopathology and alleviate memory impairments in APP-transgenic mice. Importantly, these effects are attained independently of hyperforin. Specifically, two extracts characterized by low hyperforin content (i) significantly decrease intracerebral Aβ42 levels, (ii) decrease the number and size of amyloid plaques, (iii) rescue neocortical neurons, (iv) restore cognition to normal levels, and (iv) activate microglia in vitro and in vivo. Mechanistically, we reveal that the reduction of soluble Aβ42 species is the consequence of a highly increased export activity in the bloodbrain barrier ABCC1transporter, which was found to play a fundamental role in Aβ excretion into the bloodstream. These data (i) support the significant beneficial potential of SJW extracts on AD proteopathy, and (ii) demonstrate for the first time that hyperforin concentration does not necessarily correlate with their therapeutic effects. Hence, by activating ABC transporters, specific extracts of SJW may be used to treat AD and other diseases involving peptide accumulation and cognition impairment. We propose that the anti-depressant and anti-dementia effects of these hyperforin-reduced phytoextracts could be combined for treatment of the elderly, with a concomitant reduction in deleterious hyperforin-related side effects.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Hypericum; Maze Learning; Mice; Mice, Transgenic; Microglia; Multidrug Resistance-Associated Proteins; Peptide Fragments; Phagocytes; Phloroglucinol; Phytotherapy; Plant Preparations; Plaque, Amyloid; Terpenes; Time Factors

Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antipsychotic Agents; Bromodeoxyuridine; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Doublecortin Domain Proteins; Exons; Gene Expression Regulation; Hippocampus; Humans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Mutation; Neurogenesis; Neuropeptides; Phloroglucinol; Presenilin-1; Rats; Rats, Sprague-Dawley; SOXB1 Transcription Factors; Terpenes; Time Factors

The paraventricular nucleus (PVN) of the hypothalamus is an important region of the brain involved in the regulation of sympathetic vasomotor tone. Accumulating evidence supports the idea that a change in hypothalamic γ-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory inputs contribute to the exacerbated sympathetic drive in chronic heart failure (HF). The purpose of this study was to determine whether a possible imbalance between glutamatergic and GABAergic inputs to the PVN contributes to increased sympathetic outflow in HF in two different sympathetic territories. Renal (RSNA) and splanchnic sympathetic nerve activity (SSNA), mean arterial blood pressure (MAP) and heart rate were recorded from urethane-anesthetized HF or sham rats. The NMDA-glutamate and GABA-A receptor densities within the PVN were quantified in HF and sham rats by autoradiography. Bilateral microinjection of kynurenic acid (4nmol) into the PVN decreased MAP and RSNA and SSNA in HF but not in sham rats. Furthermore, in response to GABA-A blockade in the PVN by bicuculline (400 pmol), hypertension and SSNA were reduced in HF compared to sham. The quantification of ionotropic NMDA receptors and GABA-A receptors in the PVN showed a significant reduction of GABA-A in HF rats; however, the NMDA density in the PVN did not differ between groups. Thus, this study provides evidence that the sympathoexcitation is maintained by an imbalance between GABAergic and glutamatergic inputs in the PVN in HF. The reduced GABAergic input results in relatively augmented glutamatergic actions in the PVN of HF rats.

Topics: Animals; Autoradiography; Blood Pressure; Disease Models, Animal; Dizocilpine Maleate; Echocardiography; Excitatory Amino Acid Antagonists; GABA-A Receptor Agonists; GABAergic Neurons; Heart Failure; Heart Rate; Heart Ventricles; Kidney; Kynurenic Acid; Ligation; Male; Microinjections; Muscimol; Paraventricular Hypothalamic Nucleus; Phloroglucinol; Rats; Rats, Wistar; Splanchnic Nerves; Terpenes; Tritium

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Mice; Mice, Transgenic; Phloroglucinol; Presenilin-1; Protein Processing, Post-Translational; Synaptic Transmission; tau Proteins; Terpenes

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Bridged Bicyclo Compounds; Disease Models, Animal; Encephalitis; Glial Fibrillary Acidic Protein; Gliosis; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Oxidative Stress; Phloroglucinol; Terpenes; Tyrosine

Hyperforin (Hyp) is an active compound contained in the extract of Hypericum perforatum, well known for its antidepressant activity. However, Hyp has been found to possess several other biological properties, including inhibitory effects on tumor invasion, angiogenesis, and inflammation. In this paper, we show that treatment with Hyp inhibited IFN-gamma production, with down-regulation of T-box (T-bet; marker of Th1 gene expression) and up-regulation of GATA-3 (marker gene of Th2) on IL-2/PHA-activated T cells. In parallel, we showed a strong down-regulation of the chemokine receptor CXCR3 expression on activated T cells. The latter effect and the down-modulation of matrix metalloproteinase 9 expression may eventually lead to the inhibition of migratory capability and matrix traversal toward the chemoattractant CXCL10 by activated lymphocytes that we observed in vitro. The effect of Hyp was thus evaluated on an animal model of experimental allergic encephalomyelitis (EAE), a classic, Th1-mediated autoimmune disease of the CNS, and we observed that Hyp attenuates the severity of the disease symptoms significantly. Together, these properties qualify Hyp as a putative, therapeutic molecule for the treatment of autoimmune inflammatory disease sustained by Th1 cells, including EAE.

Topics: Animals; Bridged Bicyclo Compounds; Cell Survival; Disease Models, Animal; Down-Regulation; Encephalomyelitis, Autoimmune, Experimental; Female; GATA3 Transcription Factor; Humans; Interferon-gamma; Interleukin-2; Phloroglucinol; Phytohemagglutinins; Rats; Rats, Inbred Lew; Receptors, CXCR3; T-Box Domain Proteins; T-Lymphocytes; Terpenes; Th1 Cells; Up-Regulation

The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid beta-peptide (Abeta). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Abeta-induced spatial memory impairments and on Abeta neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Abeta-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Abeta oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Abeta aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Analysis of Variance; Animals; Bridged Bicyclo Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Escape Reaction; Hippocampus; Hypericum; Male; Maze Learning; Microinjections; Neuroprotective Agents; Phloroglucinol; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Terpenes; Time Factors

Clinical studies have demonstrated that the antidepressant efficacy of Hypericum perforatum extract is comparable to that of classic antidepressants, such as imipramine. The role played by its components, particularly hypericin and hyperforin, has been examined in different experimental models of depression. The present study was carried out in order to verify the hypothesis that hyperforin is the main active antidepressant component. For this purpose we evaluated the activity of a dry extract from a subspecies of H. perforatum, H. perforatum spp. angustifolium, which has a higher hyperforin content than H. perforatum perforatum, in a series of experimental models of depression. The models used are based on the development of hyporeactivity to aversive stimuli induced by unavoidable stress exposure in rats. The extract of H. perforatum angustifolium presented an efficacy that was similar to that obtained with a treatment with imipramine or H. perforatum perforatum. Furthermore, in the models used the H. perforatum angustifolium extract was active at doses eight times lower than those necessary to produce a comparable activity with H. perforatum extract.

Topics: Animals; Antidepressive Agents; Bridged Bicyclo Compounds; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Hypericum; Imipramine; Male; Phloroglucinol; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Stress, Psychological; Terpenes

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.

Topics: Animals; Antidepressive Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Bridged Bicyclo Compounds; Chronic Disease; Depression; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Electroshock; Fluoxetine; Hypericum; Imipramine; Microdialysis; Phloroglucinol; Plant Extracts; Rats; Stress, Physiological; Terpenes