Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists
The roots and rhizomes of Valeriana jatamansi have long been used as folk medicine in Asia and usually named as “Zhizhuxiang” in Chinese for the treatment of abdominal distention and pain. However, its active ingredients and molecular targets for treatment of abdominal pain remain unrevealed. Inhibi...
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.00885/full |
| _version_ | 1811192382623842304 |
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| author | Fa-Wu Dong Fa-Wu Dong He-Hai Jiang He-Hai Jiang Liu Yang Ye Gong Cheng-Ting Zi Dan Yang Chen-Jun Ye Huan Li Jian Yang Jian Yang Yin Nian Jun Zhou Jiang-Miao Hu |
| author_facet | Fa-Wu Dong Fa-Wu Dong He-Hai Jiang He-Hai Jiang Liu Yang Ye Gong Cheng-Ting Zi Dan Yang Chen-Jun Ye Huan Li Jian Yang Jian Yang Yin Nian Jun Zhou Jiang-Miao Hu |
| author_sort | Fa-Wu Dong |
| collection | DOAJ |
| description | The roots and rhizomes of Valeriana jatamansi have long been used as folk medicine in Asia and usually named as “Zhizhuxiang” in Chinese for the treatment of abdominal distention and pain. However, its active ingredients and molecular targets for treatment of abdominal pain remain unrevealed. Inhibitors of Cav2.2 N-type voltage-gated calcium channels (VGCCs) are actively sought after for their potential in treating pain, especially chronic pain. As far as we know, the method used for seeking analgesic active ingredient from plant material has rarely been reported. The analgesic potentials of the EtOH extract (0.01 mg/ml) of the roots and rhizomes of V. jatamansi and its EtOAc, n-BuOH and H2O soluble parts (0.01 mg/ml, respectively) were tested herein on Cav2.2, using whole-oocyte recordings in vitro by tow-electrode voltage clamp. The results indicated that the EtOAc-soluble part exhibited the most potent inhibition of Cav2.2 peak current (20 mv). The EtOAc-soluble part was then subjected to silica gel column chromatography (CC) and giving 9 fractions. Phytochemical studies were carried out by repeated CC and extensive spectroscopic analyses after the fraction (0.01 mg/ml) was identified to be active and got seventeen compounds (1–17). All isolates were then sent for further bioactive verification (1 and 3 at concentration of 10 μM, others at 30 μM). In addition, the selectivity of the active compounds 1 and 3 were tested on various ion channels including Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. The results indicated that compound 1 and 3 (an abundant compound) inhibited Cav2.2 with an EC50 of 3.3 and 4.8 μM, respectively, and had weaker or no effect on Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. Compounds 1 and 3 appear to act as allosteric modulators rather than pore blockers of Cav2.2, which may play crucial role in attenuating nociception. The results of present research indicated that the ethnopharmacological utilization of V. jatamansi for relieving the abdominal distention and pain may mediate through Cav2.2 channel. Our work is the first demonstration of inhibition of Cav2.2 by iridoids, which may provide a fresh source for finding new analgesics. |
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| institution | Directory Open Access Journal |
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| last_indexed | 2024-04-11T23:51:47Z |
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| spelling | doaj.art-5d7a6c4cd7044e808dbdbbe656099b082022-12-22T03:56:28ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-08-01910.3389/fphar.2018.00885386951Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel AntagonistsFa-Wu Dong0Fa-Wu Dong1He-Hai Jiang2He-Hai Jiang3Liu Yang4Ye Gong5Cheng-Ting Zi6Dan Yang7Chen-Jun Ye8Huan Li9Jian Yang10Jian Yang11Yin Nian12Jun Zhou13Jiang-Miao Hu14State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaFaculty of Pharmacy, Yunnan University of Traditional Chinese Medicine, Kunming, ChinaKey Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaFaculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaKey Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaDepartment of Biological Sciences, Columbia University, New York, NY, United StatesKey Laboratory of Bioactive Peptides of Yunnan Province, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaState Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, ChinaThe roots and rhizomes of Valeriana jatamansi have long been used as folk medicine in Asia and usually named as “Zhizhuxiang” in Chinese for the treatment of abdominal distention and pain. However, its active ingredients and molecular targets for treatment of abdominal pain remain unrevealed. Inhibitors of Cav2.2 N-type voltage-gated calcium channels (VGCCs) are actively sought after for their potential in treating pain, especially chronic pain. As far as we know, the method used for seeking analgesic active ingredient from plant material has rarely been reported. The analgesic potentials of the EtOH extract (0.01 mg/ml) of the roots and rhizomes of V. jatamansi and its EtOAc, n-BuOH and H2O soluble parts (0.01 mg/ml, respectively) were tested herein on Cav2.2, using whole-oocyte recordings in vitro by tow-electrode voltage clamp. The results indicated that the EtOAc-soluble part exhibited the most potent inhibition of Cav2.2 peak current (20 mv). The EtOAc-soluble part was then subjected to silica gel column chromatography (CC) and giving 9 fractions. Phytochemical studies were carried out by repeated CC and extensive spectroscopic analyses after the fraction (0.01 mg/ml) was identified to be active and got seventeen compounds (1–17). All isolates were then sent for further bioactive verification (1 and 3 at concentration of 10 μM, others at 30 μM). In addition, the selectivity of the active compounds 1 and 3 were tested on various ion channels including Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. The results indicated that compound 1 and 3 (an abundant compound) inhibited Cav2.2 with an EC50 of 3.3 and 4.8 μM, respectively, and had weaker or no effect on Cav1.2, Cav2.1 and Cav3.1 VGCCs and Kv1.2, Kv2.1, Kv3.1 and BK potassium channels. Compounds 1 and 3 appear to act as allosteric modulators rather than pore blockers of Cav2.2, which may play crucial role in attenuating nociception. The results of present research indicated that the ethnopharmacological utilization of V. jatamansi for relieving the abdominal distention and pain may mediate through Cav2.2 channel. Our work is the first demonstration of inhibition of Cav2.2 by iridoids, which may provide a fresh source for finding new analgesics.https://www.frontiersin.org/article/10.3389/fphar.2018.00885/fullValeriana jatamansiiridoidabdominal distention and painN-type voltage-gated calcium channelsCav2.2 |
| spellingShingle | Fa-Wu Dong Fa-Wu Dong He-Hai Jiang He-Hai Jiang Liu Yang Ye Gong Cheng-Ting Zi Dan Yang Chen-Jun Ye Huan Li Jian Yang Jian Yang Yin Nian Jun Zhou Jiang-Miao Hu Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists Frontiers in Pharmacology Valeriana jatamansi iridoid abdominal distention and pain N-type voltage-gated calcium channels Cav2.2 |
| title | Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists |
| title_full | Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists |
| title_fullStr | Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists |
| title_full_unstemmed | Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists |
| title_short | Valepotriates From the Roots and Rhizomes of Valeriana jatamansi Jones as Novel N-Type Calcium Channel Antagonists |
| title_sort | valepotriates from the roots and rhizomes of valeriana jatamansi jones as novel n type calcium channel antagonists |
| topic | Valeriana jatamansi iridoid abdominal distention and pain N-type voltage-gated calcium channels Cav2.2 |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.00885/full |
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