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Johann Mulzer - One of the best experts on this subject based on the ideXlab platform.
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from planning to optimization total synthesis of Valerenic Acid and some bioactive derivatives
European Journal of Organic Chemistry, 2012Co-Authors: Jurgen Ramharter, Johann MulzerAbstract:A detailed study of the total synthesis of Valerenic Acid, a well known GABAA receptor subtype modulator, is described. Both successful as well as unsuccessful attempts towards the synthesis of the title compound are presented, including four different strategies to synthesize one of the key intermediates. The first two strategies are based on epoxides provided from the chiral pool, whereas the last two approaches rest on stereocontrolled modifications of 2-cyclopentenone. The streamlined synthesis implements a new one-pot reaction, which combines the addition of a Grignard species with an Acid-catalyzed isomerization of the intermediate allylic alcohol. Further highlights are a stereo- and regioselective hydroxy-directed Diels–Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. After optimization of our synthesis, the preparation of several easily available derivatives is also discussed. Amides obtained by functionalization of the carboxyl group are more than twice as active as Valerenic Acid.
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efficient and scalable one pot synthesis of 2 4 dienols from cycloalkenones optimized total synthesis of Valerenic Acid
Organic Letters, 2011Co-Authors: Jurgen Ramharter, Johann MulzerAbstract:A mild and selective one-pot procedure to provide 2,4-dienols from simple cycloalkenones in high yields is described. This transformation is based on the in situ formation of Acid-labile allylic alcohols, which on treatment with trifluoroacetic Acid undergo a formal [1,3]-hydroxy migration to form diastereo- and enantiomerically enriched 2,4-dienols. The usefulness of this protocol is demonstrated in a short synthesis of Valerenic Acid.
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Valerenic Acid derivatives as novel subunit selective gabaa receptor ligands in vitro and in vivo characterization
British Journal of Pharmacology, 2010Co-Authors: Sophia Khom, Johann Mulzer, Barbara Strommer, Jurgen Ramharter, Thomas Schwarz, Christoph Schwarzer, Thomas Erker, Gerhard F Ecker, Steffen HeringAbstract:BACKGROUND AND PURPOSE Subunit-specific modulators of γ-aminobutyric Acid (GABA) type A (GABAA) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic Acid (VA) was recently identified as a β2/3 subunit-specific modulator of GABAA receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABAA receptor modulators and to gain insight into the structure–activity relation of this molecule. EXPERIMENTAL APPROACH The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABAA receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (IGABA) through GABAA receptors (EC50) and efficacies (maximal stimulation of IGABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS Valerenic Acid amide (VA-A) displayed the highest efficacy (more than twofold greater IGABA enhancement than VA) and highest potency (EC50= 13.7 ± 2.3 µM) on α1β3 receptors. Higher efficacy and potency of VA-A were also observed on α1β2γ2s and α3β3γ2s receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS Valerenic Acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting β3 subunit containing GABAA receptors for development of anxiolytics.
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total synthesis of Valerenic Acid a potent gabaa receptor modulator
Organic Letters, 2009Co-Authors: Jurgen Ramharter, Johann MulzerAbstract:The first total synthesis of the sesquiterpenoid Valerenic Acid, a constituent of Valeriana officinalis, is described. The compound is a potent modulator of the GABAA receptor and may thus be useful in the treatment of various dysfunctions of the central nervous system. The synthesis is enantio-, diastereo-, and regiocontrolled and utilizes an enyne-RCM, a metal-coordinated Diels−Alder reaction, a hydroxy-directed Crabtree hydrogenation, and a Negishi methylation as key steps.
Jose G Ortiz - One of the best experts on this subject based on the ideXlab platform.
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Valerenic Acid and valeriana officinalis extracts delay onset of pentylenetetrazole ptz induced seizures in adult danio rerio zebrafish
BMC Complementary and Alternative Medicine, 2015Co-Authors: Bianca A Torreshernandez, Lisa M Del Vallemojica, Jose G OrtizAbstract:Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis. Our aims were to examine the anticonvulsant properties of Valerenic Acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs. All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, Valerenic Acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with Valerenic Acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic Acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p < 0.05 level of significance. All treatments were compared with the untreated animals and with the other pretreatments. After exposure to pentylenetetrazole, zebrafish exhibited a series of stereotypical behaviors prior to the appearance of clonic-like movements—convulsions. Both Valerenic Acid and valerian extracts (aqueous and ethanolic) significantly extended the latency period to the onset of seizure (convulsion) in adult zebrafish. The ethanolic valerian extract was a more potent anticonvulsant than the aqueous extract. Valerenic Acid and both valerian extracts interacted synergistically with clonazepam to extended the latency period to the onset of seizure. Phenytoin showed interaction only with the ethanolic valerian extracts. Valerenic Acid and valerian extracts have anticonvulsant properties in adult zebrafish. Valerian extracts markedly enhanced the anticonvulsant effect of both clonazepam and phenytoin, and could contribute to therapy of epileptic patients.
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Valerenic Acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish)
BMC Complementary and Alternative Medicine, 2015Co-Authors: Bianca A. Torres-hernández, Lisa M. Del Valle-mojica, Jose G OrtizAbstract:Background Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis . Our aims were to examine the anticonvulsant properties of Valerenic Acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs. Methods All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, Valerenic Acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with Valerenic Acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic Acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p
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Valerenic Acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish).
BMC Complementary and Alternative Medicine, 2015Co-Authors: Bianca A. Torres-hernández, Lisa M. Del Valle-mojica, Jose G OrtizAbstract:Anticonvulsant properties have been attributed to extracts of the herbal medicine Valeriana officinalis. Our aims were to examine the anticonvulsant properties of Valerenic Acid and valerian extracts and to determine whether valerian preparations interact with the activity of other anti-epileptic drugs (phenytoin or clonazepam). To achieve these goals, we validated the adult zebrafish, Danio rerio, as an animal model for studying anticonvulsant drugs. All drug treatments were administered by immersion in water containing the drug. For assays of anticonvulsant activity, zebrafish were pretreated with: anti-epileptic drugs, Valerenic Acid, aqueous or ethanolic valerian extracts, or mixtures (phenytoin or clonazepam with Valerenic Acid or valerian extracts). Seizures were then induced with pentylenetetrazole (PTZ). A behavioral scale was developed for scoring PTZ-induced seizures in adult zebrafish. The seizure latency was evaluated for all pretreatments and control, untreated fish. Valerenic Acid and both aqueous and ethanolic extracts of valerian root were also evaluated for their ability to improve survival after pentylenetetrazole-challenge. The assay was validated by comparison with well-studied anticonvulsant drugs (phenytoin, clonazepam, gabapentin and valproate). One-way ANOVA followed by Tukey post-hoc test was performed, using a p
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Anxiolytic properties of Valeriana officinalis in the zebrafish: a possible role for metabotropic glutamate receptors.
Planta Medica, 2012Co-Authors: Lisa M. Del Valle-mojica, Jose G OrtizAbstract:Valerian extract is used in complementary and alternative medicine for its anxiolytic and sedative properties. Our previous research demonstrated valerian interactions with glutamate receptors. The purpose of this study was to determine if valerian anxiolytic properties are mediated by metabotropic glutamate receptors (mGluR) such as mGluR (1/5) (mGluR I) and mGluR (2/3) (mGluR II). Adult wild-type zebrafish ( Danio rerio ) prefer the black compartment and avoid the white compartment in the dark/light preference task. Zebrafish exposed to 1 mg/mL of valerian extract or 0.00117 mg/mL Valerenic Acid increased their residence time in the white side by 84.61 ± 6.55 % and 58.30 ± 8.97 %, respectively. LAP3 (mGluR I antagonist) and EGLU (mGluR II antagonist) significantly inhibited the effects of valerian and Valerenic Acid. These results demonstrated that valerian and Valerenic Acid have anxiolytic properties in the zebrafish. Moreover, the selective interaction of valerian with mGluR I and II represent an alternative explanation for the anxiolytic properties of this plant and support the role of mGluR in anxiety.
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selective interactions of valeriana officinalis extracts and Valerenic Acid with 3h glutamate binding to rat synaptic membranes
Evidence-based Complementary and Alternative Medicine, 2011Co-Authors: Lisa M Del Vallemojica, Bianca A Torreshernandez, Yoshira M Ayalamarin, Carmen M Ortizsanchez, Safa Abdallamukhaimer, Jose G OrtizAbstract:Although GABA neurotransmission has been suggested as a mechanism for Valeriana officinalis effects, CNS depression can also be evoked by inhibition of ionotropic (iGluR) and metabotropic glutamate receptors (mGluR). In this study, we examined if aqueous valerian extract interacted with glutamatergic receptors. Freshly prepared aqueous valerian extract was incubated with rat cortical synaptic membranes in presence of 20 nM [3H]Glutamate. Aqueous valerian extract increased [3H]Glutamate binding from to mg/mL. In the presence of (2S,,)-2-(Carboxycyclopropyl)glycine (LCCG-I) and (2S,,)-2-(,-Dicarboxycyclopropyl)glycine (DCG-IV), Group II mGluR agents, valerian extract markedly decreased [3H]Glutamate binding, while (2S)-2-amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) propanoic Acid) (quisqualic Acid, QA), Group I mGluR agonist, increased [3H]Glutamate binding. At 0.05 mg/mL aqueous valerian extract specifically interacted with kainic Acid NMDA and AMPA receptors. Valerenic Acid, a marker compound for Valeriana officinalis, increased the [3H]Glutamate binding after mg/mL, and at 0.008 mg/mL it interacted only with QA (Group I mGluR). The selective interactions of valerian extract and Valerenic Acid with Group I and Group II mGluR may represent an alternative explanation for the anxiolytic properties of this plant.
Jurgen Ramharter - One of the best experts on this subject based on the ideXlab platform.
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from planning to optimization total synthesis of Valerenic Acid and some bioactive derivatives
European Journal of Organic Chemistry, 2012Co-Authors: Jurgen Ramharter, Johann MulzerAbstract:A detailed study of the total synthesis of Valerenic Acid, a well known GABAA receptor subtype modulator, is described. Both successful as well as unsuccessful attempts towards the synthesis of the title compound are presented, including four different strategies to synthesize one of the key intermediates. The first two strategies are based on epoxides provided from the chiral pool, whereas the last two approaches rest on stereocontrolled modifications of 2-cyclopentenone. The streamlined synthesis implements a new one-pot reaction, which combines the addition of a Grignard species with an Acid-catalyzed isomerization of the intermediate allylic alcohol. Further highlights are a stereo- and regioselective hydroxy-directed Diels–Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. After optimization of our synthesis, the preparation of several easily available derivatives is also discussed. Amides obtained by functionalization of the carboxyl group are more than twice as active as Valerenic Acid.
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efficient and scalable one pot synthesis of 2 4 dienols from cycloalkenones optimized total synthesis of Valerenic Acid
ChemInform, 2012Co-Authors: Jurgen Ramharter, Johann MulzrAbstract:The reaction of a variety of cyclic enones with Grignard or organolithium reagents proceeds via formation of intermediate allylic alcohols which further rearrange under Acidic conditions (TFA or AcOH) to afford the desired dienols.
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efficient and scalable one pot synthesis of 2 4 dienols from cycloalkenones optimized total synthesis of Valerenic Acid
Organic Letters, 2011Co-Authors: Jurgen Ramharter, Johann MulzerAbstract:A mild and selective one-pot procedure to provide 2,4-dienols from simple cycloalkenones in high yields is described. This transformation is based on the in situ formation of Acid-labile allylic alcohols, which on treatment with trifluoroacetic Acid undergo a formal [1,3]-hydroxy migration to form diastereo- and enantiomerically enriched 2,4-dienols. The usefulness of this protocol is demonstrated in a short synthesis of Valerenic Acid.
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total synthesis of Valerenic Acid a potent gabaa receptor modulator
Organic Letters, 2009Co-Authors: Jurgen Ramharter, Johann MulzerAbstract:The first total synthesis of the sesquiterpenoid Valerenic Acid, a constituent of Valeriana officinalis, is described. The compound is a potent modulator of the GABAA receptor and may thus be useful in the treatment of various dysfunctions of the central nervous system. The synthesis is enantio-, diastereo-, and regiocontrolled and utilizes an enyne-RCM, a metal-coordinated Diels−Alder reaction, a hydroxy-directed Crabtree hydrogenation, and a Negishi methylation as key steps.
Steffen Hering - One of the best experts on this subject based on the ideXlab platform.
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analysis of β subunit dependent gabaa receptor modulation and behavioral effects of Valerenic Acid derivatives
Journal of Pharmacology and Experimental Therapeutics, 2016Co-Authors: Sophia Khom, Christoph Schwarzer, Juliane Hintersteiner, Maximilian Haider, Denise Luger, Marko D Mihovilovic, Gerit Pototschnig, Steffen HeringAbstract:Valerenic Acid (VA)—a β 2/3-selective GABA type A (GABA A ) receptor modulator—displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β -subunit-dependent enhancement of GABA-induced chloride currents (I GABA ) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced I GABA enhancement was determined in oocytes expressing α 1 β 1 γ 2S, α 1 β 2 γ 2S, or α 1 β 3 γ 2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β 2/3-selective VA derivatives such as VA-amide (VA-A) modulating α 1 β 3 γ 2S (VA-A: E max = 972 ± 69%, n = 6, P α 1 β 2 γ 2S receptors (E max = 1119 ± 72%, n = 6, P α 1 β 3 γ 2S: VA: E max = 632 ± 88%, n = 9 versus α 1 β 2 γ 2S: VA: E max = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P GABA through β 3-containing receptors more efficaciously than VA (E max = 1043 ± 57%, P n = 6) displayed stronger anticonvulsive effects. Increased potency of I GABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole ( α 1 β 3 γ 2S: VA-TET: EC 50 = 6.0 ± 1.0 μ M, P P β 2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas impairment of locomotion was observed at doses ≥10 mg/kg.
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esters of Valerenic Acid as potential prodrugs
European Journal of Pharmacology, 2014Co-Authors: Juliane Hintersteiner, Gottfried Reznicek, Walter Jager, Sophia Khom, Christoph Schwarzer, Maximilian Haider, Denise Luger, Marko D Mihovilovic, Steffen HeringAbstract:Valerenic Acid (VA) is a β2/3 subunit-specific modulator of γ-aminobutyric Acid (GABA) type A (GABAA) receptors inducing anxiolysis. Here we analyze if VA-esters can serve as prodrugs and if different ester structures have different in vitro/in vivo effects. Modulation of GABAA receptors expressed in Xenopus oocytes was studied with 2-microelectrode-voltage-clamp. Anxiolytic effects of the VA-esters were studied on male C57BL/6N mice by means of the elevated plus maze-test; anticonvulsant properties were deduced from changes in seizure threshold upon pentylenetetrazole infusion. VA was detected in plasma confirming hydrolysis of the esters and release of VA in vivo. Esterification significantly reduced the positive allosteric modulation of GABAA (α1β3γ2S) receptors in vitro. in vivo, the studied VA-ester derivatives induced similar or even stronger anxiolytic and anticonvulsant action than VA. While methylation and propylation of VA resulted in faster onset of anxiolysis, the action of VA-ethylester was longer lasting, but occurred with a significant delay. The later finding is in line with the longer lasting anticonvulsant effects of this compound. The estimated VA plasma concentrations provided first insight into the release kinetics from different VA-esters. This might be an important step for its future clinical application as a potential non-sedative anxiolytic and anticonvulsant.
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Valerenic Acid derivatives as novel subunit selective gabaa receptor ligands in vitro and in vivo characterization
British Journal of Pharmacology, 2010Co-Authors: Sophia Khom, Johann Mulzer, Barbara Strommer, Jurgen Ramharter, Thomas Schwarz, Christoph Schwarzer, Thomas Erker, Gerhard F Ecker, Steffen HeringAbstract:BACKGROUND AND PURPOSE Subunit-specific modulators of γ-aminobutyric Acid (GABA) type A (GABAA) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic Acid (VA) was recently identified as a β2/3 subunit-specific modulator of GABAA receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABAA receptor modulators and to gain insight into the structure–activity relation of this molecule. EXPERIMENTAL APPROACH The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABAA receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (IGABA) through GABAA receptors (EC50) and efficacies (maximal stimulation of IGABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS Valerenic Acid amide (VA-A) displayed the highest efficacy (more than twofold greater IGABA enhancement than VA) and highest potency (EC50= 13.7 ± 2.3 µM) on α1β3 receptors. Higher efficacy and potency of VA-A were also observed on α1β2γ2s and α3β3γ2s receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS Valerenic Acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting β3 subunit containing GABAA receptors for development of anxiolytics.
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modulation of gabaa receptors by valerian extracts is related to the content of Valerenic Acid
Planta Medica, 2008Co-Authors: Gabriele Trauner, Sophia Khom, Igor Baburin, Birgit Benedek, Steffen Hering, Brigitte KoppAbstract:VALERIANA OFFICINALIS L . is a traditionally used sleep remedy, however, the mechanism of action and the substances responsible for its sedative and sleep-enhancing properties are not fully understood. As we previously identified Valerenic Acid as a subunit-specific allosteric modulator of GABA A receptors, we now investigated the relation between modulation of GABA A receptors by Valerian extracts of different polarity and the content of sesquiterpenic Acids (Valerenic Acid, acetoxyValerenic Acid). All extracts were analysed by HPLC concerning the content of sesquiterpenic Acids. GABA A receptors composed of α 1 , β 2 and γ 2S subunits were expressed in XENOPUS LAEVIS oocytes and the modulation of chloride currents through GABA A receptors (I GABA ) by Valerian extracts was investigated using the two-microelectrode voltage clamp technique. Apolar extracts induced a significant enhancement of I GABA , whereas polar extracts showed no effect. These results were confirmed by fractionating a highly active ethyl acetate extract: again fractions with high contents of Valerenic Acid exhibited strong receptor activation. In addition, removal of sesquiterpenic Acids from the ethyl acetate extract led to a loss of I GABA enhancement. In conclusion, our data show that the extent of GABA A receptor modulation by Valerian extracts is related to the content of Valerenic Acid. AVA:acetoxyValerenic Acid CNS:central nervous system EA:crude ethyl acetate extract EtOAc:ethyl acetate extract GABA:γ-amino butyric Acid GABA A receptor:GABA activated type A receptor H 2 O:distilled water extract HVA:hydroxyValerenic Acid I GABA :GABA-induced chloride current through GABA A receptors MeOH:methanol extract PE:petroleum ether extract RV:reservoir volumina TLC:thin layer chroamtography VA:Valerenic Acid VLC:vacuum liquid chromatography
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Valerenic Acid potentiates and inhibits gabaa receptors molecular mechanism and subunit specificity
Neuropharmacology, 2007Co-Authors: Sophia Khom, Gabriele Trauner, Brigitte Kopp, Igor Baburin, Eugen Timin, Annette Hohaus, Steffen HeringAbstract:Abstract Valerian is a commonly used herbal medicinal product for the treatment of anxiety and insomnia. Here we report the stimulation of chloride currents through GABAA receptors (IGABA) by Valerenic Acid (VA), a constituent of Valerian. To analyse the molecular basis of VA action, we expressed GABAA receptors with 13 different subunit compositions in Xenopus oocytes and measured IGABA using the two-microelectrode voltage-clamp technique. We report a subtype-dependent stimulation of IGABA by VA. Only channels incorporating β2 or β3 subunits were stimulated by VA. Replacing β2/3 by β1 drastically reduced the sensitivity of the resulting GABAA channels. The stimulatory effect of VA on α1β2 receptors was substantially reduced by the point mutation β2N265S (known to inhibit loreclezole action). Mutating the corresponding residue of β1 (β1S290N) induced VA sensitivity in α1β1S290N comparable to α1β2 receptors. Modulation of IGABA was not significantly dependent on incorporation of α1, α2, α3 or α5 subunits. VA displayed a significantly lower efficiency on channels incorporating α4 subunits. IGABA modulation by VA was not γ subunit dependent and not inhibited by flumazenil (1 μM). VA shifted the GABA concentration–effect curve towards lower GABA concentrations and elicited substantial currents through GABAA channels at ≥30 μM. At higher concentrations (≥100 μM), VA and acetoxy-VA inhibit IGABA. A possible open channel block mechanism is discussed. In summary, VA was identified as a subunit specific allosteric modulator of GABAA receptors that is likely to interact with the loreclezole binding pocket.
Ranbeer S. Rawal - One of the best experts on this subject based on the ideXlab platform.
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Hydrogen Peroxide Induced Deoxyribonucleic Acid Damage Preventive Activity of Selected Valeriana Species from West Himalaya
Proceedings of the National Academy of Sciences India Section B: Biological Sciences, 2017Co-Authors: Arun K. Jugran, Indra D. Bhatt, Ranbeer S. Rawal, Amit Bahukhandi, Shyamal K. NandiAbstract:The polyphenols, antioxidant activity and deoxyribonucleic Acid (DNA) damage preventive efficiency of 3 species Valeriana jatamansi , V. hardwickii and V. himalayana were investigated. V. himalayana exhibited significantly higher total phenolics and V. jatamansi showed significantly higher flavonoids and total tannins. Valerenic Acid was significantly higher in V. himalayana (1.6 %) in root portion as compared to that of V. jatamansi (0.75 %). Significantly higher antioxidant activity of 2,2′-azinobis benzyl ethyl thiazole 6-sulphonic Acid was observed as 4.65 mM AAE/100g in aerial portion and 5.73 mM AAE/100g in root portion; 2,2-diphenyl-1-picrylhydrzyl was 8.87 mM AAE/100g in aerial portion and 17.53 mM AAE/100g in root portion; and ferric reducing antioxidant power was 4.48 mM AAE/100g in aerial portion and 7.28 mM AAE/100g in root portion was higher in V. himalayana as compared to that of V. jatamansi and V. hardwickii . DNA damage preventive efficiency revealed variation in these species. V. himalayana exhibited better ability to prevent Fenton reagent induced DNA damage (97.97 %) as compared to the other two species at 100 μg/μl of aqueous extract. Based on the results it is recommended that as V. himalayana exhibited higher phytochemicals, antioxidant property and DNA damage preventive efficiency, therefore, more systematic investigation and conservation of this species is suggested to meet the increasing industrial demand. As the species is threatened in its natural habitat the other two species i.e., V. hardwickii and V. jatamansi can be promoted as an alternative source for phenolics and antioxidants.
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Impact of Altitudes and Habitats on Valerenic Acid, Total Phenolics, Flavonoids, Tannins, and Antioxidant Activity of Valeriana jatamansi
Applied Biochemistry and Biotechnology, 2016Co-Authors: Arun K. Jugran, Indra D. Bhatt, Ranbeer S. Rawal, Amit Bahukhandi, Praveen Dhyani, Shyamal K. NandiAbstract:The changes in total phenolics, flavonoids, tannins, Valerenic Acid, and antioxidant activity were assessed in 25 populations of Valeriana jatamansi sampled from 1200 to 2775 m asl and four habitat types of Uttarakhand, West Himalaya. Significant ( p
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impact of altitudes and habitats on Valerenic Acid total phenolics flavonoids tannins and antioxidant activity of valeriana jatamansi
Applied Biochemistry and Biotechnology, 2016Co-Authors: Arun K. Jugran, Indra D. Bhatt, Ranbeer S. Rawal, Amit Bahukhandi, Praveen Dhyani, Shyamal K. NandiAbstract:The changes in total phenolics, flavonoids, tannins, Valerenic Acid, and antioxidant activity were assessed in 25 populations of Valeriana jatamansi sampled from 1200 to 2775 m asl and four habitat types of Uttarakhand, West Himalaya. Significant (p < 0.05) variations in total phenolics, flavonoids, Valerenic Acid, and antioxidant activity in aerial and root portions and across the populations were observed. Antioxidant activity measured by three in vitro antioxidant assays, i.e., 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic) (ABTS) radical scavenging, 2,2′-diphenyl-1-picryylhydrazyl (DPPH) free radical scavenging, and ferric-reducing antioxidant power (FRAP) assays, showed significant (p < 0.05) differences across the populations. However, no clear pattern was found in phytochemicals across the altitudinal range. Among habitat types, (pine, oak, mixed forest, and grassy land), variation in phytochemical content and antioxidant activity were observed. Equal class ranking, neighbor-joining cluster analysis, and principal component analysis (PCA) identified Talwari, Jaberkhet, Manjkhali, and Khirshu populations as promising sources with higher phytochemicals and antioxidant activity. The results recommended that the identified populations with higher value of phytochemicals and antioxidants can be utilized for mass multiplication and breeding program to meet the domestic as well as commercial demand.
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Identification of ISSR markers associated with Valerenic Acid content and antioxidant activity in Valeriana jatamansi Jones in the West Himalaya
Molecular Breeding, 2015Co-Authors: Arun K. Jugran, Indra D. Bhatt, Ranbeer S. RawalAbstract:Valeriana jatamansi Jones, commonly known as Indian Valerian or Tagar (Family: Valerinaceae) is used in both traditional and modern systems of medicine. The plants of this species are known for their high content of Valerenic Acid, the main active constituent of valerian, and high antioxidant activity, and these characteristics have increased the demand for these plants by the pharmaceutical industry. At present, the demand for planting material is largely met from the harvesting of wild plants, which vary in quality and quantity of the active ingredient. Therefore, there is a need to identify individual plants/populations with a higher content of the active ingredients and higher antioxidant activity. We used inter-simple sequence repeats (ISSR) markers in 151 genotypes of 25 V. jatamansi populations to identify markers associated with Valerenic Acid and antioxidant activity. Of the 130 ISSR primers tested, 20 generated 159 bands, with an average of 7.95 bands per primer. Valerenic Acid content was significantly ( p
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identification of issr markers associated with Valerenic Acid content and antioxidant activity in valeriana jatamansi jones in the west himalaya
Molecular Breeding, 2015Co-Authors: Arun K. Jugran, Indra D. Bhatt, Ranbeer S. RawalAbstract:Valeriana jatamansi Jones, commonly known as Indian Valerian or Tagar (Family: Valerinaceae) is used in both traditional and modern systems of medicine. The plants of this species are known for their high content of Valerenic Acid, the main active constituent of valerian, and high antioxidant activity, and these characteristics have increased the demand for these plants by the pharmaceutical industry. At present, the demand for planting material is largely met from the harvesting of wild plants, which vary in quality and quantity of the active ingredient. Therefore, there is a need to identify individual plants/populations with a higher content of the active ingredients and higher antioxidant activity. We used inter-simple sequence repeats (ISSR) markers in 151 genotypes of 25 V. jatamansi populations to identify markers associated with Valerenic Acid and antioxidant activity. Of the 130 ISSR primers tested, 20 generated 159 bands, with an average of 7.95 bands per primer. Valerenic Acid content was significantly (p < 0.05) higher in the Katarmal (aerial portion 0.57 ± 0.04 %) and Joshimath populations (root portion 1.80 ± 0.12 %). Antioxidant activity using these different in vitro assays varied among the populations and plant portions, with maximum antioxidant activity found in the aerial plant portion (8.63 ± 0.06 mM) and roots [8.36 ± 0.0 mM ascorbic Acid equivalents (AAE)/100 g dry weight (dw)] of the Didihat and Katarmal populations, respectively, using the ABTS [2, 2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic)] assay. The DPPH (2, 2-diphenyl-1-picryylhydrazyl free radical scavenging) assay revealed maximum antioxidant activity in the aerial plant portion (15.23 ± 0.09 mM) and roots (17.53 ± 0.04 mM AAE/100 g dw) of the Didihat population. The FRAP (ferric-reducing antioxidant power) assay showed that the roots of plants of the Ukhimath population had significantly higher antioxidant activity (12.71 ± 0.04 mM AAE/100 g dw) than those of other populations of V. jatamansi. Based on the stepwise multiple regression analysis, seven positive and six negative markers showed significant association with Valerenic Acid content. Antioxidant activity measured by the ABTS, DPPH and FRAP assays showed a positive correlation with 14, 13 and 10 markers, respectively (p < 0.001). These markers have the potential for application in breeding programmes in order to select lineages of V. jatamansi with higher biochemical attributes, especially when no other genetic information, such as linkage maps and quantitative trait loci is available.
