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Moshe Rehavi - One of the best experts on this subject based on the ideXlab platform.
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Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines
Life Sciences, 2004Co-Authors: Netta Roz, Moshe RehaviAbstract:Hyperforin, a phloroglucinol derivative found in Hypericum perforatum (St. John's wort) extracts has antidepressant properties in depressed patients. Hyperforin has a unique pharmacological profile and it inhibits uptake of biogenic monoamines as well as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by Hyperforin is related to its ability to dissipate the pH gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In the present study we demonstrate that Hyperforin induces dose-dependent efflux of preloaded [3H]5HT and [3H]DA from rat brain slices. Moreover, we show that Hyperforin attenuates depolarization- dependent release of monoamines, while increasing monoamine release by amphetamine or fenfluramine. It is also demonstrated that preincubation of brain slices with reserpine is associated with dose- dependent blunting of efflux due to Hyperforin. Our data indicate that Hyperforin-induced efflux of [3H]5HT and [3H]DA reflect elevated cytoplasmic concentrations of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines.
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Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane
Life sciences, 2003Co-Authors: Netta Roz, Moshe RehaviAbstract:Abstract Extracts of Hypericum perforatum (St. John's wort) have antidepressant properties in depressed patients and exert antidepressant-like action in laboratory animals. The phloroglucinol derivative Hyperforin has become a topic of interest, as this Hypericum component is a potent inhibitor of monoamines reuptake. The molecular mechanism by which Hyperforin inhibits monoamines uptake is yet unclear. In the present study we try to clarify the mechanism by which Hyperforin inhibits the synaptic vesicle transport of monoamines. The pH gradient across the synaptic vesicle membrane, induced by vacuolar type H + -ATPase, is the major driving force for vesicular monoamines uptake and storage. We suggest that Hyperforin, like the protonophore FCCP, dissipates an existing ΔpH generated by an efflux of inwardly pumped protons. Proton transport was measured by acridine orange fluorescence quenching. Adding Mg-ATP to a medium containing 130 mM KCl and synaptic vesicles caused an immediate decrease in fluorescence of acridine orange and the addition of 1 μM FCCP abolished this effect. H + -ATPase dependent proton pumping was inhibited by Hyperforin in a dose dependent manner (IC 50 = 1.9 × 10 −7 M). Hyperforin acted similarly to the protonophore FCCP, abolishing the ATP induced fluorescence quenching (IC 50 = 4.3 × 10 −7 M). Hyperforin and FCCP had similar potencies for inhibiting rat brain synaptosomal uptake of [ 3 H]monoamines as well as vesicular monoamine uptake. The efflux of [ 3 H]5HT from synaptic vesicles was sensitive to both drugs, thus 50% of preloaded [ 3 H]5HT was released in the presence of 2.1 × 10 −7 M FCCP and 4 × 10 −7 M Hyperforin. The effect of Hyperforin on the pH gradient in synaptic vesicle membrane may explain its inhibitory effect on monoamines uptake, but could only partially explain its antidepressant properties.
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Inhibition of vesicular uptake of monoamines by Hyperforin.
Life sciences, 2002Co-Authors: Netta Roz, Yehuda Mazur, Amiram Hirshfeld, Moshe RehaviAbstract:Hyperforin is the major active ingredient of Hypericum perforatum (St John's Wort), a traditional antidepressant medication. This study evaluated its inhibitory effects on the synaptic uptake of monoamines in rat forebrain homogenates, comparing the nature of the inhibition at synaptic and vesicular monoamine transporters. A Hyperforin-rich extract inhibited with equal potencies the sodium-dependent uptake of the monoamine neurotransmitters serotonin [5-HT], dopamine [DA] and norepinephrine [NE] into rat brain synaptosomes. Hyperforin inhibited the uptake of all three monoamines noncompetitively, in marked contrast with the competitive inhibition exerted by fluoxetine, GBR12909 or desipramine on the uptake of these monoamines. Hyperforin had no inhibitory effect on the binding of [3H]paroxetine, [3H]GBR12935 and [3H]nisoxetine to membrane presynaptic transporters for 5-HT, DA and NE, respectively. The apparent presynaptic inhibition of monoamine uptake could reflect a "reserpine-like mechanism" by which Hyperforin induced release of neurotransmitters from synaptic vesicles into the cytoplasm. Thus, we assessed the effects of Hyperforin on the vesicular monoamine transporter. Hyperforin inhibited with equal potencies the uptake of the three tritiated monoamines to rat brain synaptic vesicles. Similarly to the synaptosomal uptake, the vesicular uptake was also noncompetitively inhibited by Hyperforin. Notably, Hyperforin did not affect the direct binding on [3H]dihydrotetrabenazine, a selective vesicular monoamine transporter ligand, to rat forebrain membranes. Our results support the notion that Hyperforin interferes with the storage of monoamines in synaptic vesicles, rather than being a selective inhibitor of either synaptic membrane or vesicular monoamine transporters.
Walter E. Müller - One of the best experts on this subject based on the ideXlab platform.
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Hyperforin a key constituent of st john s wort specifically activates trpc6 channels
The FASEB Journal, 2007Co-Authors: Kristina Leuner, Bettina Henke, Victor Kazanski, Margarethe Muller, Kirill Essin, Maik Gollasch, Christian Harteneck, Walter E. MüllerAbstract:Hyperforin, a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of St. John’s wort extract responsible for its antidepressive profile. Hyperforin inhibits the neur...
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Hyperforin—a key constituent of St. John’s wort specifically activates TRPC6 channels
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2007Co-Authors: Kristina Leuner, Bettina Henke, Victor Kazanski, Margarethe Muller, Kirill Essin, Maik Gollasch, Christian Harteneck, Walter E. MüllerAbstract:Hyperforin, a bicyclic polyprenylated acylphloroglucinol derivative, is the main active principle of St. John’s wort extract responsible for its antidepressive profile. Hyperforin inhibits the neur...
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Hyperforin activates nonselective cation channels (NSCCs)
British journal of pharmacology, 2005Co-Authors: Kristina Treiber, Andrea Singer, Bettina Henke, Walter E. MüllerAbstract:1 A large body of evidence supports the preclinical antidepressant profile of Hyperforin including inhibition of the synaptosomal uptake of several neurotransmitters by Hyperforin and studies in behavioural models. In contrast to other antidepressants, Hyperforin does not directly inhibit neurotransmitter transporters, but instead uptake inhibition seems to be the consequence of an elevated intracellular sodium concentration ([Na+]i). 2 The mechanism of Hyperforin-induced elevation of [Na+]i was investigated using two different cell types: human platelets and rat pheochromocytoma cells (PC12 cells). In both cell systems, Hyperforin increased both [Na+]i and free intracellular Ca2+ concentration ([Ca2+]i). 3 One pathway for Na+ and Ca2+ entry is mediated by nonselective cation channels (NSCCs), which can be blocked by SK&F 96365 and LOE 908. LOE 908 is a blocker of both NSCC1 and NSCC2 subclasses, while SK&F 96365 blocks NSCC2 only. Both SK&F 96365 and LOE 908 completely inhibited the Hyperforin-induced influx of Na+ and Ca2+ into platelets and PC12 cells. This indicates that Hyperforin is mainly active upon NSCC2. 4 The effect of Hyperforin is inhibited by La3+ and Gd3+, indicating that there is a potential homology with canonical transient receptor potential protein channels (TRPC channels). Moreover, La3+ and Gd3+ attenuate the effect of Hyperforin on serotonin uptake in human platelets. Additionally, Hyperforin induces barium influx in PC12 cells and this influx can be inhibited by SK&F 96365, LOE 908, Gd3+ and La3+. 5 In summary, these findings suggest that Hyperforin represents a new principle for preclinical antidepressant activity, modulating brain neurotransmission by inhibition of neurotransmitter uptake via activation of NSCCs. British Journal of Pharmacology (2005) 145, 75–83. doi:10.1038/sj.bjp.0706155
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Hyperforin modifies neuronal membrane properties in vivo.
Neuroscience letters, 2004Co-Authors: Gunter P. Eckert, Jan-henning Keller, Claudia Jourdan, Michael Karas, Dietrich A. Volmer, Manfred Schubert-zsilavecz, Walter E. MüllerAbstract:Hyperforin, the major active constituent of St. John Wort (SJW) extract, affects several neurotransmitter systems in the brain putatively by modulation of the physical state of neuronal membranes. Accordingly, we tested the effects of SJW extract and of Hyperforin on the properties of murine brain membrane fluidity. Oral administration of SJW extract and of Hyperforin sodium salt results in significant Hyperforin brain levels. Treatment of mice with Hyperforin leads to decreased annular- and bulk fluidity and increased acyl-chain flexibility of brain membranes. All Hyperforin related changes of membrane properties were significantly correlated with the corresponding Hyperforin brain levels. Our data emphasises a membrane interaction of Hyperforin that possibly contributes to its pharmacological effects.
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Enhancement of proteolytic processing of the β-amyloid precursor protein by Hyperforin
Biochemical Pharmacology, 2003Co-Authors: Bettina Froestl, Barbara Steiner, Walter E. MüllerAbstract:Abstract We studied the effect of Hyperforin, a component of St. John’s wort ( Hypericum perforatum ) extracts, on the processing of the amyloid precursor protein (APP) in rat pheochromocytoma PC12 cells, stably transfected with human wildtype APP. We observed transiently increased release of secretory APP fragments upon Hyperforin treatment. Unique features, like a strong reduction of intracellular APP and the time course of soluble APP release, distinguished the effects of Hyperforin from those of alkalizing agents and phorbol esters, well known activators of secretory processing of APP. Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), a protonophore, induced an almost identical decrease in intracellular pH in PC12 cells as does Hyperforin. Despite this, FCCP induced a less pronounced release of soluble APP fragments and only slightly reduced intracellular APP levels. These results suggest that Hyperforin is an activator of secretory processing of APP with a novel mechanism of action not solely dependent on its effects on intracellular pH.
Netta Roz - One of the best experts on this subject based on the ideXlab platform.
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Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines
Life Sciences, 2004Co-Authors: Netta Roz, Moshe RehaviAbstract:Hyperforin, a phloroglucinol derivative found in Hypericum perforatum (St. John's wort) extracts has antidepressant properties in depressed patients. Hyperforin has a unique pharmacological profile and it inhibits uptake of biogenic monoamines as well as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by Hyperforin is related to its ability to dissipate the pH gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In the present study we demonstrate that Hyperforin induces dose-dependent efflux of preloaded [3H]5HT and [3H]DA from rat brain slices. Moreover, we show that Hyperforin attenuates depolarization- dependent release of monoamines, while increasing monoamine release by amphetamine or fenfluramine. It is also demonstrated that preincubation of brain slices with reserpine is associated with dose- dependent blunting of efflux due to Hyperforin. Our data indicate that Hyperforin-induced efflux of [3H]5HT and [3H]DA reflect elevated cytoplasmic concentrations of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines.
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Hyperforin inhibits vesicular uptake of monoamines by dissipating pH gradient across synaptic vesicle membrane
Life sciences, 2003Co-Authors: Netta Roz, Moshe RehaviAbstract:Abstract Extracts of Hypericum perforatum (St. John's wort) have antidepressant properties in depressed patients and exert antidepressant-like action in laboratory animals. The phloroglucinol derivative Hyperforin has become a topic of interest, as this Hypericum component is a potent inhibitor of monoamines reuptake. The molecular mechanism by which Hyperforin inhibits monoamines uptake is yet unclear. In the present study we try to clarify the mechanism by which Hyperforin inhibits the synaptic vesicle transport of monoamines. The pH gradient across the synaptic vesicle membrane, induced by vacuolar type H + -ATPase, is the major driving force for vesicular monoamines uptake and storage. We suggest that Hyperforin, like the protonophore FCCP, dissipates an existing ΔpH generated by an efflux of inwardly pumped protons. Proton transport was measured by acridine orange fluorescence quenching. Adding Mg-ATP to a medium containing 130 mM KCl and synaptic vesicles caused an immediate decrease in fluorescence of acridine orange and the addition of 1 μM FCCP abolished this effect. H + -ATPase dependent proton pumping was inhibited by Hyperforin in a dose dependent manner (IC 50 = 1.9 × 10 −7 M). Hyperforin acted similarly to the protonophore FCCP, abolishing the ATP induced fluorescence quenching (IC 50 = 4.3 × 10 −7 M). Hyperforin and FCCP had similar potencies for inhibiting rat brain synaptosomal uptake of [ 3 H]monoamines as well as vesicular monoamine uptake. The efflux of [ 3 H]5HT from synaptic vesicles was sensitive to both drugs, thus 50% of preloaded [ 3 H]5HT was released in the presence of 2.1 × 10 −7 M FCCP and 4 × 10 −7 M Hyperforin. The effect of Hyperforin on the pH gradient in synaptic vesicle membrane may explain its inhibitory effect on monoamines uptake, but could only partially explain its antidepressant properties.
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Inhibition of vesicular uptake of monoamines by Hyperforin.
Life sciences, 2002Co-Authors: Netta Roz, Yehuda Mazur, Amiram Hirshfeld, Moshe RehaviAbstract:Hyperforin is the major active ingredient of Hypericum perforatum (St John's Wort), a traditional antidepressant medication. This study evaluated its inhibitory effects on the synaptic uptake of monoamines in rat forebrain homogenates, comparing the nature of the inhibition at synaptic and vesicular monoamine transporters. A Hyperforin-rich extract inhibited with equal potencies the sodium-dependent uptake of the monoamine neurotransmitters serotonin [5-HT], dopamine [DA] and norepinephrine [NE] into rat brain synaptosomes. Hyperforin inhibited the uptake of all three monoamines noncompetitively, in marked contrast with the competitive inhibition exerted by fluoxetine, GBR12909 or desipramine on the uptake of these monoamines. Hyperforin had no inhibitory effect on the binding of [3H]paroxetine, [3H]GBR12935 and [3H]nisoxetine to membrane presynaptic transporters for 5-HT, DA and NE, respectively. The apparent presynaptic inhibition of monoamine uptake could reflect a "reserpine-like mechanism" by which Hyperforin induced release of neurotransmitters from synaptic vesicles into the cytoplasm. Thus, we assessed the effects of Hyperforin on the vesicular monoamine transporter. Hyperforin inhibited with equal potencies the uptake of the three tritiated monoamines to rat brain synaptic vesicles. Similarly to the synaptosomal uptake, the vesicular uptake was also noncompetitively inhibited by Hyperforin. Notably, Hyperforin did not affect the direct binding on [3H]dihydrotetrabenazine, a selective vesicular monoamine transporter ligand, to rat forebrain membranes. Our results support the notion that Hyperforin interferes with the storage of monoamines in synaptic vesicles, rather than being a selective inhibitor of either synaptic membrane or vesicular monoamine transporters.
Alexandre Bouron - One of the best experts on this subject based on the ideXlab platform.
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Hyperforin Potentiates Antidepressant-Like Activity of Lanicemine in Mice
Frontiers in Molecular Neuroscience, 2018Co-Authors: Bartłomiej Pochwat, Alexandre Bouron, Bernadeta Szewczyk, Anna Rafało-ulińska, Katarzyna Kotarska, Marcin Siwiec, Joanna E. Sowa, Krzysztof Tokarski, Agata Siwek, Kristina FriedlandAbstract:N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca2+ dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel, and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression. The objective of the present study was to determine the antidepressant effects of either a single dose of Hyperforin or lanicemine vs. their combined effects in mice. Hyperforin modulates intracellular Ca2+ levels by activating Ca2+-conducting non-selective canonical transient receptor potential 6 channel (TRPC6) channels. Lanicemine, on the other hand, blocks NMDARs and regulates Ca2+ dependent processes. To evaluate the antidepressant-like activity of Hyperforin and lanicemine, a set of in vivo (behavioral) and in vitro methods (western blotting, Ca2+ imaging studies, electrophysiological, and radioligand binding assays) was employed. Combined administration of Hyperforin and lanicemine evoked long-lasting antidepressant-like effects in both naïve and chronic corticosterone-treated mice while also enhancing the expression of the synapsin I, GluA1 subunit, and brain derived neurotrophic factor (BDNF) proteins in the frontal cortex. In Ca2+ imaging studies, lanicemine enhanced Ca2+ influx induced by Hyperforin. Moreover, compound such as MK-2206 (Akt kinase inhibitor) inhibited the antidepressant-like activity of Hyperforin in the tail suspension test (TST). Hyperforin reversed disturbances induced by MK-801 in the novel object recognition (NOR) test and had no effects on NMDA currents and binding to NMDAR. Our results suggest that co-administration of Hyperforin and lanicemine induces long-lasting antidepressant effects in mice and that both substances may have different molecular targets.
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Hyperforin Potentiates Antidepressant-Like Activity of Lanicemine in Mice.
Frontiers in molecular neuroscience, 2018Co-Authors: Bartłomiej Pochwat, Alexandre Bouron, Bernadeta Szewczyk, Anna Rafało-ulińska, Katarzyna Kotarska, Marcin Siwiec, Krzysztof Tokarski, Agata Siwek, Joanna Sowa, Kristina FriedlandAbstract:N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca2+ dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression. The objective of the present study was to determine the antidepressant effects of either a single dose of Hyperforin or lanicemine versus their combined effects in mice. Hyperforin modulates intracellular Ca2+ levels by activating Ca2+-conducting the non-selective canonical transient receptor potential 6 channel (TRPC6) channels. Lanicemine, on the other hand, blocks NMDARs and regulates Ca2+ dependent processes. To evaluate the antidepressant-like activity of Hyperforin and lanicemine, a set of in vivo (behavioral) and in vitro methods (western blotting, Ca2+ imaging studies, electrophysiological and radioligand binding assays) was employed. Combined administration of Hyperforin and lanicemine evoked long-lasting antidepressant-like effects in both naive and chronic corticosterone-treated mice while also enhancing the expression of the synapsin I, GluA1 subunit and brain derived neurotrophic factor (BDNF) proteins in the frontal cortex. In Ca2+ imaging studies, lanicemine enhanced Ca2+ influx induced by Hyperforin. Moreover, compounds such as MK-2206 (Akt kinase inhibitor) inhibited the antidepressant-like activity of Hyperforin in the tail suspension test (TST). Hyperforin reversed disturbances induced by MK-801 in the novel object recognition (NOR) test and had no effects on NMDA currents and binding to NMDAR. Our results suggest that co-administration of Hyperforin and lanicemine induces long-lasting antidepressant effects in mice and that both substances may have different molecular targets.
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Data_Sheet_1_Hyperforin Potentiates Antidepressant-Like Activity of Lanicemine in Mice.PDF
2018Co-Authors: Bartłomiej Pochwat, Alexandre Bouron, Bernadeta Szewczyk, Anna Rafało-ulińska, Katarzyna Kotarska, Marcin Siwiec, Joanna E. Sowa, Krzysztof Tokarski, Agata Siwek, Kristina FriedlandAbstract:N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca2+ dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel, and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression. The objective of the present study was to determine the antidepressant effects of either a single dose of Hyperforin or lanicemine vs. their combined effects in mice. Hyperforin modulates intracellular Ca2+ levels by activating Ca2+-conducting non-selective canonical transient receptor potential 6 channel (TRPC6) channels. Lanicemine, on the other hand, blocks NMDARs and regulates Ca2+ dependent processes. To evaluate the antidepressant-like activity of Hyperforin and lanicemine, a set of in vivo (behavioral) and in vitro methods (western blotting, Ca2+ imaging studies, electrophysiological, and radioligand binding assays) was employed. Combined administration of Hyperforin and lanicemine evoked long-lasting antidepressant-like effects in both naïve and chronic corticosterone-treated mice while also enhancing the expression of the synapsin I, GluA1 subunit, and brain derived neurotrophic factor (BDNF) proteins in the frontal cortex. In Ca2+ imaging studies, lanicemine enhanced Ca2+ influx induced by Hyperforin. Moreover, compound such as MK-2206 (Akt kinase inhibitor) inhibited the antidepressant-like activity of Hyperforin in the tail suspension test (TST). Hyperforin reversed disturbances induced by MK-801 in the novel object recognition (NOR) test and had no effects on NMDA currents and binding to NMDAR. Our results suggest that co-administration of Hyperforin and lanicemine induces long-lasting antidepressant effects in mice and that both substances may have different molecular targets.
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[Cellular and molecular effects of the antidepressant Hyperforin on brain cells: Review of the literature].
L'Encéphale, 2014Co-Authors: Alexandre Bouron, Eric LorrainAbstract:INTRODUCTION: Hypericum perforatum is, with Ginkgo biloba, one of the most frequently prescribed medicinal plants in the world. Its popular name, St. John's wort (SJW), is due to the fact that its flowers, yellow, are gathered around the feast of St. John the Baptist (24th June) whereas "wort" is an old English word for plant. Of interest, SJW possesses antidepressant actions and is currently used to alleviate symptoms of mild to moderate depression. Nearly two dozens of bioactive compounds have been isolated from SJW. Hypericin, originally described as a monoamine oxidase inhibitor type A, was thought to be responsible for the antidepressant properties of SJW extracts. However, subsequent studies could not confirm this observation and Hyperforin, a phloroglucinol derivative, was shown to display antidepressive properties. Indeed, the efficiency of the extracts of SJW has been reported to be dependent on the concentration of Hyperforin. However, its effects on brain cells and on the mechanisms underlying its putative clinical antidepressant effect remain poorly characterized. OBJECTIVE: The aim of this review article is to propose an overview of the recent scientific publications that have provided new and relevant insights into the neurobiological actions of Hyperforin. RESULTS: Hyperforin has been described as an inhibitor of the reuptake of many neurotransmitters such as dopamine, norepinephrine, serotonin or glutamate. It is thus a potent modulator of synaptic transmission. In addition, it blocks the activity of many receptors such as gamma-aminobutyric acid (GABA) and N-Methyl-D-aspartate (NMDA) receptors. More recently, Hyperforin has been shown to activate TRPC6, a Ca(2+)-conducting channel of the plasma membrane, which is the only channel opened by this molecule. Interestingly, the other transient receptor potential channels of C type (TRPC) isoforms (TRPC1, TRPC3, TRPC4, TRPC5 and TRPC7) are insensitive to Hyperforin. Due to this specific property, it is now used as a convenient pharmacological tool to investigate the functions of endogenous TRPC6 channels in various cell types. Chronically applied to neuronal cell line PC12, Hyperforin promotes the extension of neurites via a mechanism implying TRPC6 channels. It is also known to trigger an intracellular signalling pathway that involves the cAMP-dependent protein kinase A and the transcription factor cyclic adenosine monophosphate response element binding protein (CREB). This leads to an up-regulation of the expression of the brain-derived neurotrophic factor (BDNF) receptor neurotrophic tyrosine kinase (TrkB) and TRPC6. This Hyperforin-dependent cascade is controlled by Ca(2+) ions and occurs specifically in the cortex but not in the hippocampus. One key aspect of the cellular responses induced by Hyperforin is its impact on the homeostasis of several cations (Na(+), Ca(2+), Zn(2+) and H(+)). In vitro experiments demonstrated that Hyperforin, which changes the fluidity of membranes, elevates the intracellular concentration of these elements by promoting their influx and/or their release from internal compartments. CONCLUSION: The phloroglucinol derivative Hyperforin is an important bioactive molecule of Hypericum perforatum exhibiting antidepressive properties. Although it inhibits the reuptake of many neurotransmitters, Hyperforin is in fact a multi-target drug influencing the cellular homeostatic mechanisms of Ca(2+), Zn(2+), H(+) and Na(+) due to its effects on their influx and/or release from internal stores. In addition, Hyperforin is a potent modulator of mitochondrial functions. In spite of recent progress in the characterization of the cellular Hyperforin responses, it remains unclear what pharmacological aspects of Hyperforin functions are relevant in vivo.
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The antidepressant Hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner.
International Journal of Neuropsychopharmacology, 2012Co-Authors: Julien Gibon, Jean-christophe Deloulme, Tiphaine Chevallier, Elodie Ladevèze, Djoher Nora Abrous, Alexandre BouronAbstract:Hyperforin is one of the main bioactive compounds that underlie the antidepressant actions of the medicinal plant Hypericum perforatum (St. John's wort). However, the effects of a chronic Hyperforin treatment on brain cells remains to be fully addressed. The following study was undertaken to further advance our understanding of the biological effects of this plant extract on neurons. Special attention was given to its impact on the brain-derived neurotrophic factor (BDNF) receptor TrkB and on adult hippocampal neurogenesis since they appear central to the mechanisms of action of antidepressants. The consequences of a chronic Hyperforin treatment were investigated on cortical neurons in culture and on the brain of adult mice treated for 4 wk with a daily injection (i.p.) of Hyperforin (4 mg/kg). Its effects on the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phospho-CREB (p-CREB), TrkB and phospho-TrkB (p-TrkB) were analysed by Western blot experiments and its impact on adult hippocampal neurogenesis was also investigated. Hyperforin stimulated the expression of TRPC6 channels and TrkB via SKF-96365-sensitive channels controlling a downstream signalling cascade involving Ca2+, protein kinase A, CREB and p-CREB. In vivo, Hyperforin augmented the expression of TrkB in the cortex but not in the hippocampus where hippocampal neurogenesis remained unchanged. In conclusion, this plant extract acts on the cortical BDNF/TrkB pathway leaving adult hippocampal neurogenesis unaffected. This study provides new insights on the neuronal responses controlled by Hyperforin. We propose that the cortex is an important brain structure targeted by Hyperforin.
Andrew J Mclachlan - One of the best experts on this subject based on the ideXlab platform.
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understanding drug interactions with st john s wort hypericum perforatum l impact of Hyperforin content
Journal of Pharmacy and Pharmacology, 2019Co-Authors: Sigrun Chrubasikhausmann, Julia Vlachojannis, Andrew J MclachlanAbstract:OBJECTIVE The aim of this study was to review herb-drug interaction studies with St John's wort (Hypericum perforatum L.) with a focus on the Hyperforin content of the extracts used in these studies. METHODS PUBMED was systematically searched to identify studies describing pharmacokinetic interactions involving St John's wort. Data on study design and the St John's wort extract or product were gathered to extract Hyperforin content and daily dose used in interaction studies. KEY FINDINGS This analysis demonstrates that significant herb-drug interactions (resulting in a substantial change in systemic exposure) with St John's wort products were associated with Hyperforin daily dosage. Products that had a daily dose of <1 mg Hyperforin were less likely to be associated with major interaction for drugs that were CYP3A4 or p-glycoprotein substrates. Although a risk of interactions cannot be excluded even for low-dose Hyperforin St. John's wort extracts, the use of products that result in a dose of not more than 1 mg Hyperforin per day is recommended to minimise the risk of interactions. CONCLUSIONS This review highlights that the significance of herb-drug interactions with St John's wort is influenced by the nature of the herbal medicines product, particularly the Hyperforin content.