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Saini RS, Binduhayyim RIH, Kuruniyan MS, Heboyan A. In silico exploration of bioactive secondary metabolites with anesthetic effects on sodium channels Nav 1.7, 1.8, and 1.9 in painful human dental pulp. Mol Pain 2025; 21:17448069251327824. [PMID: 40070109 PMCID: PMC11938900 DOI: 10.1177/17448069251327824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/16/2025] [Accepted: 02/27/2025] [Indexed: 03/25/2025] Open
Abstract
AIM To investigate the efficacy of medicinal plant bioactive secondary metabolites as inhibitors of voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) in managing painful states of dental pulps. METHODOLOGY Molecular docking, ADME prediction, toxicity profiling, and pharmacophore modeling were used to assess the binding affinities, pharmacokinetic properties, toxicological profiles, and active pharmacophores of the selected bioactive compounds. RESULTS Three compounds (Sepaconitine, Lappaconitine, and Ranaconitine) showed binding affinities (ΔG = -8.95 kcal/mol, -7.77 kcal/mol, and -7.44 kcal/mol, respectively) with all three Nav1.7, Nav1.8, and Nav1.9 sodium channels. The sepaconitine amine group formed hydrophobic interactions with key residues. The Lappaconitine benzene ring contributed to hydrophobic interactions and hydrogen bond acceptor interactions. The hydrophobic interactions of the ranaconitine amine group play a critical role with specific residues on Nav1.8 and Nav1.9. CONCLUSION The natural fusicoccane diterpenoid derivatives Sepaconitine, Lappaconitine, and Ranaconitine are potential lead compounds for the development of novel analgesics as selective antihyperalgesic drugs, which will provide a new dental pharmacological intervention for managing painful dental pulp conditions. Further experimental validation and clinical studies that confirm the efficacy and safety of these compounds will strengthen their applicability in dental practice.
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Affiliation(s)
- Ravinder S Saini
- Department of Allied Dental Health Sciences, COAMS, King Khalid University, Abha, Saudi Arabia
| | | | | | - Artak Heboyan
- Department of Prosthodontics, Faculty of Stomatology, Yerevan State Medical University after Mkhitar Heratsi, Yerevan, Armenia
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Wei S, Liu TT, Hu WP, Qiu CY. Resveratrol inhibits the activity of acid-sensing ion channels in male rat dorsal root ganglion neurons. J Neurosci Res 2022; 100:1755-1764. [PMID: 35592934 DOI: 10.1002/jnr.25060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/16/2022] [Accepted: 04/22/2022] [Indexed: 11/07/2022]
Abstract
Resveratrol can relieve pain under various pain conditions. One of the mechanisms of resveratrol analgesia is the regulation of ion channels. Acid-sensing ion channels (ASICs) are expressed predominantly in nociceptive sensory neurons to detect changes in extracellular pH. ASICs are important players in pain associated with tissue acidification. However, it is still unclear whether ASICs are resveratrol targets. Electrophysiological recordings showed that resveratrol decreased acid-induced and ASIC-mediated currents in male rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner. Resveratrol downwardly shifted the concentration-response curve for protons, suggesting that it inhibited ASICs not by changing the pH0.5 , but by suppressing the proton-induced maximum response. It also suppressed acid-triggered action potentials in the rat DRG neurons. Finally, intraplantar pretreatment with resveratrol relieved acid-induced nociceptive responses in male rats in a dose-dependent manner. These results indicated that resveratrol inhibited ASIC-mediated electrophysiological activity and nociception, suggesting a novel peripheral mechanism underlying its analgesic effect.
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Affiliation(s)
- Shuang Wei
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.,School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China
| | - Ting-Ting Liu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China
| | - Wang-Ping Hu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.,Department of Physiology, Hubei College of Chinese Medicine, Jingzhou, PR China
| | - Chun-Yu Qiu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.,School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China
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Zhang LL, Qiu J, Hong JR, Xu XQ, Zhang GQ, Li G. Magnolol attenuates inflammatory pain by inhibiting sodium currents in mouse dorsal root ganglion neurons. Inflammopharmacology 2021; 29:869-877. [PMID: 34021831 DOI: 10.1007/s10787-021-00809-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 04/05/2021] [Indexed: 10/21/2022]
Abstract
Voltage-gated sodium channels are currently recognized as one of the targets of analgesics. Magnolol (Mag), an active component isolated from Magnolia officinalis, has been reported to exhibit analgesic effects. The objective of this study was to investigate whether the analgesic effect of Mag was associated with blocking Na+ channels. Inflammatory pain was induced by the injection of carrageenan into the hind paw of mice. Mag was administered orally. Mechanical hyperanalgesia was evaluated by using von Frey filaments. Na+ currents and neuronal excitability in acutely isolated mouse dorsal root ganglion (DRG) neurons were recorded with the whole-cell patch clamp technique. Results showed that Mag (10 ~ 40 mg/kg) dose-dependently inhibited the paw edema and reduced mechanical pain in the inflammatory animal model. Injection of carrageenan significantly increased the amplitudes of TTX-sensitive and TTX-resistant Na+ currents. Compared with the carrageenan group, Mag inhibited the upregulation of two types of Na+ currents induced by carrageenan in a dose-dependent manner. Mag 40 mg/kg shifted the inactivation curves of two types of Na+ currents to hyperpolarization and returned to normal animal level without changing their activation curves. Mag 40 mg/kg significantly reduced the percentage of cells firing multiple spikes and inhibited the neuronal hyperexcitability induced by carrageenan. Our data suggest that the analgesic effect of Mag may be associated with a decreased neuronal excitability by blocking Na+ current.
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Affiliation(s)
- Lu-Lu Zhang
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jie Qiu
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jiang-Ru Hong
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiu-Qi Xu
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Guang-Qin Zhang
- Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Guang Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research of Southwest, Medical University, Luzhou, 646000, China.
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Modulations of Na v1.8 and Na v1.9 Channels in Monosodium Urate-Induced Gouty Arthritis in Mice. Inflammation 2021; 44:1405-1415. [PMID: 33515125 DOI: 10.1007/s10753-021-01425-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 01/03/2021] [Accepted: 01/21/2021] [Indexed: 10/22/2022]
Abstract
The aim of the present study was to observe the changes of TTX-R, Nav1.8, and Nav1.9 Na+ currents in MSU-induced gouty arthritis mice, and to explore the possibility of Nav1.8 and Nav1.9 channels as potential targets for gout pain treatment. Acute gouty arthritis was induced by monosodium urate (MSU) in mice. Swelling degree was evaluated by measuring the circumference of the ankle joint. Mechanical allodynia was assessed by applying the electronic von Frey. Na+ currents were recorded by patch-clamp techniques in acute isolated dorsal root ganglion (DRG) neurons. MSU treatment significantly increased the swelling degree of ankle joint and decreased the mechanical pain threshold. The amplitude of TTX-R Na+ current was significantly increased and reached its peak on the 4th day after injection of MSU. For TTX-R Na+ channel subunits, Nav1.8 current density was significantly increased, but Nav1.9 current density was markedly decreased after MSU treatment. MSU treatment shifted the steady-state activation curves of TTX-R Na+ channel, Nav1.8 and Nav1.9 channels, and the inactivation curves of TTX-R Na+ channel and Nav1.8 channels to the depolarizing direction, but did not affect the inactivation curve of Nav1.9 channel. Compared with the normal group, the recovery of Nav1.8 channel was faster, while that of Nav1.9 channel was slower. The recovery of TTX-R Na+ channel remained unchanged after MSU treatment. Additionally, MSU treatment increased DRG neurons excitability by reducing action potential threshold. Nav1.8 channel, not Nav1.9 channel, may be involved in MSU-induced gout pain by increasing nerve excitability.
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Shu FQ, Lu YG, Tang HP, Ye ZY, Huang YN, Wang M, Tang ZQ, Chen L. Resveratrol noncompetitively inhibits glycine receptor-mediated currents in neurons of rat central auditory neurons. Brain Res Bull 2021; 169:18-24. [PMID: 33400956 DOI: 10.1016/j.brainresbull.2020.12.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/21/2020] [Accepted: 12/30/2020] [Indexed: 01/17/2023]
Abstract
Resveratrol, a naturally occurring stilbene found in red wine, is known to modulate the activity of several types of ion channels and membrane receptors, including Ca2+, K+, and Na+ ion channels. However, little is known about the effects of resveratrol on some important receptors, such as glycine receptors and GABAA receptors, in the central nervous system (CNS). In the present study, the effects of resveratrol on glycine receptor or GABAA receptor-mediated currents in cultured rat inferior colliculus (IC) and auditory cortex (AC) neurons were studied using whole-cell voltage-clamp recordings. Resveratrol itself did not evoke any currents in IC neurons but it reversibly decreased the amplitude of glycine-induced current (IGly) in a concentration-dependent manner. Resveratrol did not change the reversal potential of IGly but it shifted the concentration-response relationship to the right without changing the Hill coefficient and with decreasing the maximum response of IGly. Interestingly, resveratrol inhibited the amplitude of IGly but not that of GABA-induced current (IGABA) in AC neurons. More importantly, resveratrol inhibited GlyR-mediated but not GABAAR-mediated inhibitory postsynaptic currents in IC neurons using brain slice recordings. Together, these results demonstrate that resveratrol noncompetitively inhibits IGly in auditory neurons by decreasing the affinity of glycine to its receptor. These findings suggest that the native glycine receptors but not GABAA receptors in central neurons are targets of resveratrol during clinical administrations.
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Affiliation(s)
- Fang-Qi Shu
- School of Life Sciences, Anhui University, Hefei, 230601, China; Key Laboratory of Human Microenvironment and Precision Medicine of Anhui Higher Education Institutes, Anhui University, Hefei, 230601, China
| | - Yun-Gang Lu
- CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China; Auditory Research Laboratory, University of Science and Technology of China, Hefei, 230027, China
| | - Hui-Ping Tang
- CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China; Auditory Research Laboratory, University of Science and Technology of China, Hefei, 230027, China
| | - Zeng-You Ye
- CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China
| | - Yi-Na Huang
- CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China; Auditory Research Laboratory, University of Science and Technology of China, Hefei, 230027, China
| | - Ming Wang
- CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China; Auditory Research Laboratory, University of Science and Technology of China, Hefei, 230027, China
| | - Zheng-Quan Tang
- School of Life Sciences, Anhui University, Hefei, 230601, China; Key Laboratory of Human Microenvironment and Precision Medicine of Anhui Higher Education Institutes, Anhui University, Hefei, 230601, China.
| | - Lin Chen
- CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China; Auditory Research Laboratory, University of Science and Technology of China, Hefei, 230027, China.
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Okubo N, Ishikawa H, Sano R, Shimazu Y, Takeda M. Effect of resveratrol on the hyperexcitability of nociceptive neurons associated with ectopic hyperalgesia induced by experimental tooth movement. Eur J Oral Sci 2020; 128:275-283. [PMID: 33856731 DOI: 10.1111/eos.12722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2020] [Indexed: 11/28/2022]
Abstract
The present study investigated whether, under in vivo conditions, systemic administration of resveratrol attenuates the experimental tooth movement-induced ectopic hyperalgesia associated with hyperexcitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) neurons. The threshold of escape from mechanical stimulation applied to the ipsilateral whisker pad in rats exposed to experimental tooth movement was significantly lower than seen in control rats from day 1 to 3 following movement of the right maxillary first molar tooth. The lowered mechanical threshold in the rats exposed to experimental tooth movement had almost returned to the level of sham-treated naïve rats at day 3 following administration of resveratrol. The mean mechanical threshold of nociceptive SpVc neurons was significantly lower after experimental tooth movement but the lower threshold could be reversed by administration of resveratrol. The higher discharge frequency of nociceptive SpVc neurons for noxious mechanical stimuli observed in rats exposed to experimental tooth movement was statistically significantly lower following resveratrol administration. These results suggest that resveratrol attenuates experimental tooth movement-induced mechanical ectopic hyperalgesia via suppression of peripheral and/or central sensitization. These findings support the idea that resveratrol, a complementary alternative medicine, is a potential therapeutic agent for the prevention of experimental tooth movement-induced ectopic hyperalgesia.
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Affiliation(s)
- Nao Okubo
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Japan
| | - Haruna Ishikawa
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Japan
| | - Rena Sano
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Japan
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Japan
| | - Mamoru Takeda
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Japan
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Takeda M, Shimazu Y. Modulatory mechanism underlying how dietary constituents attenuate orofacial pain. J Oral Sci 2020; 62:140-143. [DOI: 10.2334/josnusd.19-0224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Mamoru Takeda
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University
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Nieoczym D, Socała K, Jedziniak P, Wyska E, Wlaź P. Effect of Pterostilbene, a Natural Analog of Resveratrol, on the Activity of some Antiepileptic Drugs in the Acute Seizure Tests in Mice. Neurotox Res 2019; 36:859-869. [PMID: 30877660 PMCID: PMC6831770 DOI: 10.1007/s12640-019-00021-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 02/08/2023]
Abstract
Pterostilbene (PTE), a natural analog of resveratrol, is available both as a diet ingredient and a dietary supplement. The present study was undertaken to assess the effect of PTE on the activity of antiepileptic drugs in the acute seizure tests in mice, i.e., the intravenous pentetrazole (iv PTZ) seizure threshold, maximal electroshock (MES), and 6 Hz-induced psychomotor seizure tests. Our study revealed that PTE enhanced the anticonvulsant effect of clonazepam but did not change the activity of tiagabine in the iv PTZ test. In the MES test, PTE increased the effect of carbamazepine but did not affect the protective properties of topiramate, while in the 6-Hz test, we noted a significant enhancement of the activity of oxcarbazepine, but there were no changes in the activity of valproate. Interactions of PTE with carbamazepine and oxcarbazepine were pharmacokinetic, which was determined by the increase of concentration of these antiepileptic drugs both in the serum and brain. In contrast, interactions between PTE and clonazepam were pharmacodynamic since there were no changes in the concentration of clonazepam. Combined treatment with carbamazepine and PTE significantly attenuated muscular strength (estimated in the grip strength test) but did not change motor coordination (assessed in the chimney test) in mice. Other studied antiepileptic drugs and their combinations with PTE did not change these parameters. Further studies are required to evaluate the influence of PTE on the activity of anticonvulsant drugs to estimate the safety of using PTE by patients with epilepsy.
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Affiliation(s)
- Dorota Nieoczym
- Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland.
| | - Katarzyna Socała
- Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland
| | - Piotr Jedziniak
- Department of Pharmacology and Toxicology, National Veterinary Research Institute, Puławy, Poland
| | - Elżbieta Wyska
- Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, Kraków, Poland
| | - Piotr Wlaź
- Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland
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Cheikh A, Tabka H, Tlili Y, Santulli A, Bouzouaya N, Bouhaouala-Zahar B, Benkhalifa R. Xenopus Oocyte's Conductance for Bioactive Compounds Screening and Characterization. Int J Mol Sci 2019; 20:ijms20092083. [PMID: 31035589 PMCID: PMC6539028 DOI: 10.3390/ijms20092083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/05/2019] [Accepted: 04/08/2019] [Indexed: 12/23/2022] Open
Abstract
Background: Astaxanthin (ATX) is a lipophilic compound found in many marine organisms. Studies have shown that ATX has many strong biological properties, including antioxidant, antiviral, anticancer, cardiovascular, anti-inflammatory, neuro-protective and anti-diabetic activities. However, no research has elucidated the effect of ATX on ionic channels. ATX can be extracted from shrimp by-products. Our work aims to characterize ATX cell targets to lend value to marine by-products. Methods: We used the Xenopus oocytes cell model to characterize the pharmacological target of ATX among endogenous Xenopus oocytes’ ionic channels and to analyze the effects of all carotenoid-extract samples prepared from shrimp by-products using a supercritical fluid extraction (SFE) method. Results: ATX inhibits amiloride-sensitive sodium conductance, xINa, in a dose-dependent manner with an IC50 of 0.14 µg, a maximum inhibition of 75% and a Hill coefficient of 0.68. It does not affect the potential of half activation, but significantly changes the kinetics, according to the slope factor values. The marine extract prepared from shrimp waste at 10 µg inhibits xINa in the same way as ATX 0.1 µg does. When ATX was added to the entire extract at 10 µg, inhibition reached that induced with ATX 1 µg. Conclusions: ATX and the shrimp Extract inhibit amiloride-sensitive sodium channels in Xenopus oocytes and the TEVC method makes it possible to measure the ATX inhibitory effect in bioactive SFE-Extract samples.
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Affiliation(s)
- Amani Cheikh
- Laboratoire Venins et Molécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, 13 Place Pasteur BP74, Tunis 1002, Tunisia.
| | - Hager Tabka
- Laboratoire Venins et Molécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, 13 Place Pasteur BP74, Tunis 1002, Tunisia.
| | - Yassine Tlili
- Laboratoire Venins et Molécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, 13 Place Pasteur BP74, Tunis 1002, Tunisia.
| | - Andrea Santulli
- Laboratorio di Biochimica Marina ed ecotossicologia, Dipartimento di Scienze della Terra e del Mare, Università degli Studi di Palermo, 91100 Trapani, Italy.
| | | | - Balkiss Bouhaouala-Zahar
- Laboratoire Venins et Molécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, 13 Place Pasteur BP74, Tunis 1002, Tunisia.
- Faculté de Médecine de Tunis, Université Tunis El Manar, 15 Rue Djebel Lakhdhar, La Rabta, Tunis 1007, Tunisia.
| | - Rym Benkhalifa
- Laboratoire Venins et Molécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, 13 Place Pasteur BP74, Tunis 1002, Tunisia.
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Syoji Y, Kobayashi R, Miyamura N, Hirohara T, Kubota Y, Uotsu N, Yui K, Shimazu Y, Takeda M. Suppression of hyperexcitability of trigeminal nociceptive neurons associated with inflammatory hyperalgesia following systemic administration of lutein via inhibition of cyclooxygenase-2 cascade signaling. J Inflamm (Lond) 2018; 15:24. [PMID: 30498399 PMCID: PMC6258298 DOI: 10.1186/s12950-018-0200-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 11/14/2018] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Lutein is a dietary constituent known to inhibit inflammation; however, its effect on nociceptive neuron-associated hyperalgesia remains to be determined. The present study therefore investigated under in vivo conditions whether administration of lutein attenuates the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons that is associated with mechanical hyperalgesia. RESULTS Complete Freund's adjuvant (CFA) was injected into the whisker pads of rats to induce inflammation, and then mechanical stimulation was applied to the orofacial area to assess the threshold of escape. The mechanical threshold was significantly lower in inflamed rats compared to uninjected naïve rats, and this lowered threshold was returned to control levels by 3 days after administration of lutein (10 mg/Kg, i.p.) Also the lutein administration, inflammation-induced thickness of edema was returned to control levels. The mean increased number of cyclooxygenase-2 (Cox-2)-immunoreactive cells in the whisker pads of inflamed rats was also returned to control levels by administration with lutein. The mean discharge frequency of SpVc wide-dynamic range (WDR) neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after lutein administration. In addition, the increased mean spontaneous discharge of SpVc WDR in inflamed rats was significantly decreased after lutein administration. Similarly, lutein significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, lutein restored the expanded mean size of the receptive field in inflamed rats to control levels. CONCLUSION These results together suggest that administration of lutein attenuates inflammatory hyperalgesia associated with hyperexcitability of nociceptive SpVc WDR neurons via inhibition of the peripheral Cox-2 signaling cascade. These findings support the proposed potential of lutein as a therapeutic agent in complementary alternative medicine strategies for preventing inflammatory mechanical hyperalgesia.
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Affiliation(s)
- Yumiko Syoji
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201 Japan
| | - Ryota Kobayashi
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201 Japan
| | - Nako Miyamura
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201 Japan
| | - Tsukasa Hirohara
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201 Japan
| | - Yoshiko Kubota
- FANCL Health Science Research Center, Research Institute, FANCL Corporation, 12-13, Kamishinano, Totsuka-ku, Yokohama, Kanagawa 244-0806 Japan
| | - Nobuo Uotsu
- FANCL Health Science Research Center, Research Institute, FANCL Corporation, 12-13, Kamishinano, Totsuka-ku, Yokohama, Kanagawa 244-0806 Japan
| | - Kei Yui
- FANCL Health Science Research Center, Research Institute, FANCL Corporation, 12-13, Kamishinano, Totsuka-ku, Yokohama, Kanagawa 244-0806 Japan
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201 Japan
| | - Mamoru Takeda
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201 Japan
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Singh AK, Kumar S, Vinayak M. Recent development in antihyperalgesic effect of phytochemicals: anti-inflammatory and neuro-modulatory actions. Inflamm Res 2018; 67:633-654. [PMID: 29767332 DOI: 10.1007/s00011-018-1156-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/04/2018] [Accepted: 05/08/2018] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Pain is an unpleasant sensation triggered by noxious stimulation. It is one of the most prevalent conditions, limiting productivity and diminishing quality of life. Non steroidal anti inflammatory drugs (NSAIDs) are widely used as pain relievers in present day practice as pain is mostly initiated due to inflammation. However, due to potentially serious side effects, long term use of these antihyperalgesic drugs raises concern. Therefore there is a demand to search novel medicines with least side effects. Herbal products have been used for centuries to reduce pain and inflammation, and phytochemicals are known to cause fewer side effects. However, identification of active phytochemicals of herbal medicines and clear understanding of the molecular mechanism of their action is needed for clinical acceptance. MATERIALS AND METHODS In this review, we have briefly discussed the cellular and molecular changes during hyperalgesia via inflammatory mediators and neuro-modulatory action involved therein. The review includes 54 recently reported phytochemicals with antihyperalgesic action, as per the literature available with PubMed, Google Scholar and Scopus. CONCLUSION Compounds of high interest as potential antihyperalgesic agents are: curcumin, resveratrol, capsaicin, quercetin, eugenol, naringenin and epigallocatechin gallate (EGCG). Current knowledge about molecular targets of pain and their regulation by these phytochemicals is elaborated and the scope of further research is discussed.
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Affiliation(s)
- Ajeet Kumar Singh
- Department of Zoology, Biochemistry and Molecular Biology Laboratory, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.,Department of Zoology, CMP Degree College, University of Allahabad, Allahabad, 211002, India
| | - Sanjay Kumar
- Department of Zoology, Biochemistry and Molecular Biology Laboratory, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Manjula Vinayak
- Department of Zoology, Biochemistry and Molecular Biology Laboratory, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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12
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Food pyramid for subjects with chronic pain: foods and dietary constituents as anti-inflammatory and antioxidant agents. Nutr Res Rev 2018; 31:131-151. [PMID: 29679994 DOI: 10.1017/s0954422417000270] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Emerging literature suggests that diet constituents may play a modulatory role in chronic pain (CP) through management of inflammation/oxidative stress, resulting in attenuation of pain. We performed a narrative review to evaluate the existing evidence regarding the optimum diet for the management of CP, and we built a food pyramid on this topic. The present review also describes the activities of various natural compounds contained in foods (i.e. phenolic compounds in extra-virgin olive oil (EVO)) listed on our pyramid, which have comparable effects to drug management therapy. This review included 172 eligible studies. The pyramid shows that carbohydrates with low glycaemic index should be consumed every day (three portions), together with fruits and vegetables (five portions), yogurt (125 ml), red wine (125 ml) and EVO; weekly: legumes and fish (four portions); white meat, eggs and fresh cheese (two portions); red or processed meats (once per week); sweets can be consumed occasionally. The food amounts are estimates based on nutritional and practical considerations. At the top of the pyramid there is a pennant: it means that CP subjects may need a specific customised supplementation (vitamin B12, vitamin D, n-3 fatty acids, fibre). The food pyramid proposal will serve to guide dietary intake with to the intent of alleviating pain in CP patients. Moreover, a targeted diet can also help to solve problems related to the drugs used to combat CP, i.e. constipation. However, this paper would be an early hypothetical proposal due to the limitations of the studies.
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Tsuchiya H. Anesthetic Agents of Plant Origin: A Review of Phytochemicals with Anesthetic Activity. Molecules 2017; 22:E1369. [PMID: 28820497 PMCID: PMC6152143 DOI: 10.3390/molecules22081369] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 08/17/2017] [Accepted: 08/17/2017] [Indexed: 12/15/2022] Open
Abstract
The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na⁺ channels, γ-aminobutyric acid type A receptors, N-methyl-d-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin.
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Affiliation(s)
- Hironori Tsuchiya
- Department of Dental Basic Education, Asahi University School of Dentistry, 1851 Hozumi, Mizuho, Gifu 501-0296, Japan.
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14
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Matsumoto Y, Komatsu K, Shimazu Y, Takehana S, Syouji Y, Kobayashi A, Takeda M. Effect of resveratrol onc-fosexpression of rat trigeminal spinal nucleus caudalis and C1 dorsal horn neurons following mustard oil-induced acute inflammation. Eur J Oral Sci 2017; 125:338-344. [DOI: 10.1111/eos.12362] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Yasuhiro Matsumoto
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
| | - Kyouhei Komatsu
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
| | - Shiori Takehana
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
| | - Yumiko Syouji
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
| | - Ayumu Kobayashi
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
| | - Mamoru Takeda
- Laboratory of Food and Physiological Sciences; Department of Life and Food Sciences; School of Life and Environmental Sciences; Azabu University; Sagamihara Kanagawa Japan
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15
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Kokuba S, Takehana S, Oshima K, Shimazu Y, Takeda M. Systemic administration of the dietary constituent resveratrol inhibits the nociceptive jaw-opening reflex in rats via the endogenous opioid system. Neurosci Res 2017; 119:1-6. [PMID: 28153523 DOI: 10.1016/j.neures.2017.01.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Revised: 12/29/2016] [Accepted: 01/23/2017] [Indexed: 11/15/2022]
Abstract
The aim of the present study was to investigate whether, under in vivo conditions, systemic administration of resveratrol could attenuate the rat nociceptive jaw-opening reflex (JOR) via the endogenous opioid system. The JOR evoked by electrical stimulation of the tongue was recorded as digastric muscle electromyograms (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG increased significantly in proportion to the intensity of electrical stimulation (from 1× to 5 × threshold for the JOR). dEMG amplitude in response to 3× threshold electrical stimulation of the tongue was dose-dependently inhibited by intravenous administration of resveratrol (0.5-2mg/kg). Maximum inhibition of dEMG amplitude was seen within approximately 10min. These inhibitory effects were reversible, with dEMG responses returning to control levels after approximately 20min. Pretreatment of rats with naloxone resulted in significant, dose-dependent attenuation of the inhibitory effects of resveratrol on dEMG amplitude compared with control. These findings suggest that resveratrol inhibits the nociceptive JOR via the endogenous opioid system. Further, the findings of the present study strongly support the idea that resveratrol, which is not known to have any toxic side effects, combined with an opioid could be a potential therapeutic agent for the prevention of acute trigeminal nociception.
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Affiliation(s)
- Shota Kokuba
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan
| | - Shiori Takehana
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan
| | - Katsuo Oshima
- Department of Dental Technology, The Nippon Dental University College at Tokyo, 2-3-16, Fujimi-cho, Chiyoda-ku 102-007, Japan
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan
| | - Mamoru Takeda
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
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16
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Asiedu MN, Han C, Dib-Hajj SD, Waxman SG, Price TJ, Dussor G. The AMPK Activator A769662 Blocks Voltage-Gated Sodium Channels: Discovery of a Novel Pharmacophore with Potential Utility for Analgesic Development. PLoS One 2017; 12:e0169882. [PMID: 28118359 PMCID: PMC5261566 DOI: 10.1371/journal.pone.0169882] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 12/23/2016] [Indexed: 12/12/2022] Open
Abstract
Voltage-gated sodium channels (VGSC) regulate neuronal excitability by governing action potential (AP) generation and propagation. Recent studies have revealed that AMP-activated protein kinase (AMPK) activators decrease sensory neuron excitability, potentially by preventing sodium (Na+) channel phosphorylation by kinases such as ERK or via modulation of translation regulation pathways. The direct positive allosteric modulator A769662 displays substantially greater efficacy than other AMPK activators in decreasing sensory neuron excitability suggesting additional mechanisms of action. Here, we show that A769662 acutely inhibits AP firing stimulated by ramp current injection in rat trigeminal ganglion (TG) neurons. PT1, a structurally dissimilar AMPK activator that reduces nerve growth factor (NGF) -induced hyperexcitability, has no influence on AP firing in TG neurons upon acute application. In voltage-clamp recordings, application of A769662 reduces VGSC current amplitudes. These findings, based on acute A769662 application, suggest a direct channel blocking effect. Indeed, A769662 dose-dependently blocks VGSC in rat TG neurons and in Nav1.7-transfected cells with an IC50 of ~ 10 μM. A769662 neither displayed use-dependent inhibition nor interacted with the local anesthetic (LA) binding site. Popliteal fossa administration of A769662 decreased noxious thermal responses with a peak effect at 5 mins demonstrating an analgesic effect. These data indicate that in addition to AMPK activation, A769662 acts as a direct blocker/modulator of VGSCs, a potential mechanism enhancing the analgesic property of this compound.
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Affiliation(s)
- Marina N. Asiedu
- University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America
- University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, Texas, United States of America
| | - Chongyang Han
- Yale School of Medicine, Department of Neurology, Center for Neuroscience and Regeneration Research, and Veterans Administration Connecticut Healthcare System, Rehabilitation Research Center, West Haven, Connecticut, United States of America
| | - Sulayman D. Dib-Hajj
- Yale School of Medicine, Department of Neurology, Center for Neuroscience and Regeneration Research, and Veterans Administration Connecticut Healthcare System, Rehabilitation Research Center, West Haven, Connecticut, United States of America
| | - Stephen G. Waxman
- Yale School of Medicine, Department of Neurology, Center for Neuroscience and Regeneration Research, and Veterans Administration Connecticut Healthcare System, Rehabilitation Research Center, West Haven, Connecticut, United States of America
| | - Theodore J. Price
- University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America
- University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, Texas, United States of America
| | - Gregory Dussor
- University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America
- University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, Texas, United States of America
- * E-mail:
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17
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Takeda M, Takehana S, Sekiguchi K, Kubota Y, Shimazu Y. Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol. Int J Mol Sci 2016; 17:ijms17101702. [PMID: 27727178 PMCID: PMC5085734 DOI: 10.3390/ijms17101702] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/04/2016] [Accepted: 10/05/2016] [Indexed: 11/16/2022] Open
Abstract
Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM) candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM.
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Affiliation(s)
- Mamoru Takeda
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
| | - Shiori Takehana
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
| | - Kenta Sekiguchi
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
| | - Yoshiko Kubota
- FANCL Health Science Research Center, Research Institute, FANCL corporation, 12-13, Kamishinano, Totsuka-ku, Yokohama, Kanagawa 244-0806, Japan.
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
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18
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Local administration of resveratrol inhibits excitability of nociceptive wide-dynamic range neurons in rat trigeminal spinal nucleus caudalis. Brain Res Bull 2016; 124:262-8. [PMID: 27288246 DOI: 10.1016/j.brainresbull.2016.06.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 05/28/2016] [Accepted: 06/06/2016] [Indexed: 11/20/2022]
Abstract
Although we recently reported that intravenous administration of resveratrol suppresses trigeminal nociception, the precise peripheral effect of resveratrol on nociceptive and non-nociceptive mechanical stimulation-induced trigeminal neuron activity in vivo remains to be determined. The aim of the present study was to investigate whether local subcutaneous administration of resveratrol attenuates mechanical stimulation-induced excitability of trigeminal spinal nucleus caudalis (SpVc) neuron activity in rats, in vivo. Extracellular single-unit recordings were made of SpVc wide-dynamic range (WDR) neuron activity in response to orofacial mechanical stimulation in pentobarbital-anesthetized rats. Neurons responded to non-noxious and noxious mechanical stimulation applied to the orofacial skin. Local subcutaneous administration of resveratrol (1-10mM) into the orofacial skin dose dependently and significantly reduced the mean number of SpVc WDR neurons firing in response to both non-noxious and noxious mechanical stimuli, with the maximal inhibition of discharge frequency in response to both stimuli being seen within 5min. These inhibitory effects were no longer evident after approximately 20min. The mean magnitude of inhibition by resveratrol (10mM) of SpVc neuron discharge frequency was almost equal to that of the local anesthetic 1% lidocaine (37mM). These results suggest that local injection of resveratrol into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via inhibition of Na(+) channels in the nociceptive nerve terminals of trigeminal ganglion neurons. Therefore, local subcutaneous administration of resveratrol may provide relief of trigeminal nociceptive pain, without side effects, thus contributing to the suite of complementary and alternative medicines used as local anesthetic agents.
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Wang YJ, Chan MH, Chen L, Wu SN, Chen HH. Resveratrol attenuates cortical neuron activity: roles of large conductance calcium-activated potassium channels and voltage-gated sodium channels. J Biomed Sci 2016; 23:47. [PMID: 27209372 PMCID: PMC4875746 DOI: 10.1186/s12929-016-0259-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 05/06/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Resveratrol, a phytoalexin found in grapes and red wine, exhibits diverse pharmacological activities. However, relatively little is known about whether resveratrol modulates the ion channels in cortical neurons. The large-conductance calcium-activated potassium channels (BKCa) and voltage-gated sodium channels were expressed in cortical neurons and play important roles in regulation of neuronal excitability. The present study aimed to determine the effects of resveratrol on BKCa currents and voltage-gated sodium currents in cortical neurons. RESULTS Resveratrol concentration-dependently increased the current amplitude and the opening activity of BKCa channels, but suppressed the amplitude of voltage-gated sodium currents. Similar to the BKCa channel opener NS1619, resveratrol decreased the firing rate of action potentials. In addition, the enhancing effects of BKCa channel blockers tetraethylammonium (TEA) and paxilline on action potential firing were sensitive to resveratrol. Our results indicated that the attenuation of action potential firing rate by resveratrol might be mediated through opening the BKCa channels and closing the voltage-gated sodium channels. CONCLUSIONS As BKCa channels and sodium channels are critical molecular determinants for seizure generation, our findings suggest that regulation of these two channels in cortical neurons probably makes a considerable contribution to the antiseizure activity of resveratrol.
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Affiliation(s)
- Ya-Jean Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County, 35053, Taiwan
| | - Ming-Huan Chan
- Institute of Neuroscience, National Chengchi University, 64, Sec.2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan
- Research Center for Mind, Brain, and Learning, National Chengchi University, 64, Sec.2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan
| | - Linyi Chen
- Institute of Molecular Medicine, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu, 30013, Taiwan
| | - Sheng-Nan Wu
- Department of Physiology, National Cheng Kung University Medical College, 1 University Road, Tainan City, 70101, Taiwan.
| | - Hwei-Hisen Chen
- Center for Neuropsychiatric Research, National Health Research Institutes, 35, Keyan Road, Zhunan, Miaoli County, 35053, Taiwan.
- Institute of Neuroscience, National Chengchi University, 64, Sec.2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan.
- Department of Pharmacology and Toxicology, School of Medicine, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan.
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Sekiguchi K, Takehana S, Shibuya E, Matsuzawa N, Hidaka S, Kanai Y, Inoue M, Kubota Y, Shimazu Y, Takeda M. Resveratrol attenuates inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis neurons associated with hyperalgesia in rats. Mol Pain 2016; 12:12/0/1744806916643082. [PMID: 27068286 PMCID: PMC4956177 DOI: 10.1177/1744806916643082] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 02/23/2016] [Indexed: 01/18/2023] Open
Abstract
Background Resveratrol, a component of red wine, has been reported to decrease prostaglandin E2 production by inhibiting the cyclooxygenase-2 cascade and to modulate various voltage-dependent ion channels, suggesting that resveratrol could attenuate inflammatory hyperalgesia. However, the effects of resveratrol on inflammation-induced hyperexcitability of nociceptive neurons in vivo remain to be determined. Thus, the aim of the present study was to determine whether daily systemic administration of resveratrol to rats attenuates the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis wide-dynamic range neurons associated with hyperalgesia. Results Inflammation was induced by injection of complete Freund’s adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to whisker pad in inflamed rats was significantly lower than in control rats. The decreased mechanical threshold in inflamed rats was restored to control levels by daily systemic administration of resveratrol (2 mg/kg, i.p.). The mean discharge frequency of spinal trigeminal nucleus caudalis wide-dynamic range neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after resveratrol administration. In addition, the increased mean spontaneous discharge of spinal trigeminal nucleus caudalis wide-dynamic range neurons in inflamed rats was significantly decreased after resveratrol administration. Similarly, resveratrol significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, resveratrol restored the expanded mean size of the receptive field in inflamed rats to control levels. Conclusion These results suggest that chronic administration of resveratrol attenuates inflammation-induced mechanical inflammatory hyperalgesia and that this effect is due primarily to the suppression of spinal trigeminal nucleus caudalis wide dynamic range neuron hyperexcitability via inhibition of both peripheral and central cyclooxygenase-2 cascade signaling pathways. These findings support the idea of resveratrol as a potential complementary and alternative medicine for the treatment of trigeminal inflammatory hyperalgesia without side effects.
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Affiliation(s)
- Kenta Sekiguchi
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Shiori Takehana
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Eri Shibuya
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Nichiwa Matsuzawa
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Shiori Hidaka
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Yurie Kanai
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Maki Inoue
- Laboratory of Physiology II, Department of Veterinary Science, School of Veterinary medicine, Azabu University, Sagamihara, Kanagawa, Japan
| | - Yoshiko Kubota
- FANCL Health Science Research Center, Research Institute, FANCL Corporation, Yokohama, Kanagawa, Japan
| | - Yoshihito Shimazu
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
| | - Mamoru Takeda
- Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan
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Singh AK, Vinayak M. Anti-Nociceptive Effect of Resveratrol During Inflammatory Hyperalgesia via Differential Regulation of pro-Inflammatory Mediators. Phytother Res 2016; 30:1164-71. [DOI: 10.1002/ptr.5624] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 02/21/2016] [Accepted: 03/16/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Ajeet Kumar Singh
- Biochemistry and Molecular Biology Laboratory, Centre for Advanced Study in Zoology; Banaras Hindu University; Varanasi India
| | - Manjula Vinayak
- Biochemistry and Molecular Biology Laboratory, Centre for Advanced Study in Zoology; Banaras Hindu University; Varanasi India
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22
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Activation of Adenosine Monophosphate-activated Protein Kinase Suppresses Neuroinflammation and Ameliorates Bone Cancer Pain: Involvement of Inhibition on Mitogen-activated Protein Kinase. Anesthesiology 2016; 123:1170-85. [PMID: 26378398 DOI: 10.1097/aln.0000000000000856] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception and the attenuation of morphine antinociceptive tolerance. In this study, the authors investigated the impact of AMPK activation through resveratrol treatment on bone cancer pain. METHODS The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 8). Cytokine expression was measured using quantitative polymerase chain reaction (n = 8). Cell signalings were assayed by western blot (n = 4) and immunohistochemistry (n = 5). The microglial cell line BV-2, primary astrocytes, and neuron-like SH-SY5Y cells were cultured to investigate the in vitro effects. RESULTS Resveratrol and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide, the AMPK activators, significantly attenuated bone cancer pain in rats with tumor cell implantation (TCI; threshold of mechanical withdrawal, resveratrol vs. vehicle: 10.1 ± 0.56 vs. 4.1 ± 0.37; 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide vs. vehicle: 8.2 ± 0.17 vs. 4.1 ± 0.37, mean ± SEM); these effects were reversed by the AMPK inhibitor compound C (compound C vs. resveratrol: 6.2 ± 1.35 vs. 10.1 ± 0.56, mean ± SEM). Resveratrol has an AMPK-dependent inhibitory effect on TCI-evoked astrocyte and microglial activation. The antinociceptive effects of resveratrol were partially mediated by the reduced phosphorylation of mitogen-activated protein kinases and decreased production of proinflammatory cytokines in an AMPK-dependent manner. Furthermore, resveratrol potently inhibited inflammatory factors-mediated protein kinase B/mammalian target of rapamycin signaling in neurons. Acute pain evoked by proinflammatory cytokines in the spinal cord was significantly attenuated by resveratrol. CONCLUSIONS AMPK activation in the spinal glia by resveratrol may have utility in the treatment of TCI-induced neuroinflammation, and our results further implicate AMPK as a novel target for the attenuation of bone cancer pain.
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Takehana S, Sekiguchi K, Inoue M, Kubota Y, Ito Y, Yui K, Shimazu Y, Takeda M. Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats. Brain Res Bull 2016; 120:117-22. [DOI: 10.1016/j.brainresbull.2015.11.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 11/12/2015] [Accepted: 11/16/2015] [Indexed: 11/30/2022]
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Fraser SP, Hemsley F, Djamgoz MBA. Caffeic acid phenethyl ester: Inhibition of metastatic cell behaviours via voltage-gated sodium channel in human breast cancer in vitro. Int J Biochem Cell Biol 2015; 71:111-118. [PMID: 26724521 DOI: 10.1016/j.biocel.2015.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/09/2015] [Accepted: 12/21/2015] [Indexed: 11/28/2022]
Abstract
Caffeic acid phenethyl ester, derived from natural propolis, has been reported to have anti-cancer properties. Voltage-gated sodium channels are upregulated in many cancers where they promote metastatic cell behaviours, including invasiveness. We found that micromolar concentrations of caffeic acid phenethyl ester blocked voltage-gated sodium channel activity in several invasive cell lines from different cancers, including breast (MDA-MB-231 and MDA-MB-468), colon (SW620) and non-small cell lung cancer (H460). In the MDA-MB-231 cell line, which was adopted as a 'model', long-term (48 h) treatment with 18 μM caffeic acid phenethyl ester reduced the peak current density by 91% and shifted steady-state inactivation to more hyperpolarized potentials and slowed recovery from inactivation. The effects of long-term treatment were also dose-dependent, 1 μM caffeic acid phenethyl ester reducing current density by only 65%. The effects of caffeic acid phenethyl ester on metastatic cell behaviours were tested on the MDA-MB-231 cell line at a working concentration (1 μM) that did not affect proliferative activity. Lateral motility and Matrigel invasion were reduced by up to 14% and 51%, respectively. Co-treatment of caffeic acid phenethyl ester with tetrodotoxin suggested that the voltage-gated sodium channel inhibition played a significant intermediary role in these effects. We conclude, first, that caffeic acid phenethyl ester does possess anti-metastatic properties. Second, the voltage-gated sodium channels, commonly expressed in strongly metastatic cancers, are a novel target for caffeic acid phenethyl ester. Third, more generally, ion channel inhibition can be a significant mode of action of nutraceutical compounds.
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Affiliation(s)
- Scott P Fraser
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK.
| | - Faye Hemsley
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK
| | - Mustafa B A Djamgoz
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK; Biotechnology Research Centre (BRC), Cyprus International University, Haspolat, Lefkosa, North Cyprus, Mersin 10, Turkey
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Meftahi G, Ghotbedin Z, Eslamizade MJ, Hosseinmardi N, Janahmadi M. Suppressive Effects of Resveratrol Treatment on The Intrinsic Evoked Excitability of CA1 Pyramidal Neurons. CELL JOURNAL 2015; 17:532-9. [PMID: 26464825 PMCID: PMC4601874 DOI: 10.22074/cellj.2015.13] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 08/31/2014] [Indexed: 12/19/2022]
Abstract
Objective Resveratrol, a phytoalexin, has a wide range of desirable biological actions.
Despite a growing body of evidence indicating that resveratrol induces changes in neu-
ronal function, little effort, if any, has been made to investigate the cellular effect of res-
veratrol treatment on intrinsic neuronal properties.
Materials and Methods This experimental study was performed to examine the
acute effects of resveratrol (100 µM) on the intrinsic evoked responses of rat Cornu
Ammonis (CA1) pyramidal neurons in brain slices, using whole cell patch clamp re-
cording under current clamp conditions.
Results Findings showed that resveratrol treatment caused dramatic changes in
evoked responses of pyramidal neurons. Its treatment induced a significant (P<0.05)
increase in the after hyperpolarization amplitude of the first evoked action potential.
Resveratrol-treated cells displayed a significantly broader action potential (AP) when
compared with either control or vehicle-treated groups. In addition, the mean instantaneous firing frequency between the first two action potentials was significantly lower in
resveratrol-treated neurons. It also caused a significant reduction in the time to maximum decay of AP. The rheobase current and the utilization time were both significantly
greater following resveratrol treatment. Neurons exhibited a significantly depolarized
voltage threshold when exposed to resveratrol.
Conclusion Results provide direct electrophysiological evidence for the inhibitory
effects of resveratrol on pyramidal neurons, at least in part, by reducing the evoked
neural activity.
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Affiliation(s)
- Gholamhossein Meftahi
- Neuroscience Research Center and Department of Physiology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran ; Neuroscience Research Center, Baqiyatallah (a.s.) University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Javad Eslamizade
- Shefa Neuroscience Research Center, Khatam Al Anbia Hospital, Tehran, Iran ; Department of Neuroscience, School of Advanced Medical Technology, Iran University of Medical Sciences, Tehran, Iran
| | - Narges Hosseinmardi
- Neuroscience Research Center and Department of Physiology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahyar Janahmadi
- Neuroscience Research Center and Department of Physiology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Fraser SP, Peters A, Fleming-Jones S, Mukhey D, Djamgoz MBA. Resveratrol: Inhibitory Effects on Metastatic Cell Behaviors and Voltage-Gated Na+Channel Activity in Rat Prostate Cancer In Vitro. Nutr Cancer 2014; 66:1047-58. [DOI: 10.1080/01635581.2014.939291] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Abstract
Peanuts are important dietary food source of resveratrol with potent antioxidant properties implicated in reducing risk of cancer, cardiovascular and Alzheimer's disease, and delaying aging. Resveratrol is a naturally occurring stilbene phytoalexin phenolic compound produced in response to a variety of biotic and abiotic stresses. This paper is a review of trans-resveratrol and related stilbenes from peanuts--their chemical structures, mechanisms for their biosynthesis, and concentrations in comparison with other major food sources. It will also discuss trans-resveratrol's absorption, bioavailability, and major health benefits; processes to enhance their biosynthesis in peanuts by biotic and abiotic stresses; process optimization for enhanced levels in peanuts and their potential food applications; and methods used for its extraction and analysis.
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Affiliation(s)
- Jocelyn M Sales
- a Department of Food Science and Technology, The University of Georgia , Griffin , GA , 30223-1797 , USA
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Han Y, Jiang C, Tang J, Wang C, Wu P, Zhang G, Liu W, Jamangulova N, Wu X, Song X. Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. Eur J Pain 2014; 18:1458-70. [PMID: 24756886 DOI: 10.1002/ejp.511] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of 5' adenosine monophosphate-activated protein kinase (AMPK) activator resveratrol and AICAR to inhibit microglial activation and to limit the decrease in antinociceptive effects of morphine. METHODS The microglial cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using the hot plate and tail-flick tests. RESULTS (1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase phosphorylation, nuclear factor-κB translocation and mRNA expression of pro-inflammatory cytokines [including interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α], inducible nitric oxide synthase and Toll-like receptor-4, and these changes are inhibited by resveratrol. (2) Resveratrol activates AMPK to suppress morphine-induced BV-2 cell activation. AICAR, another AMPK activator, can mimic the effects of resveratrol, whereas compound C, an AMPK inhibitor, reverses the inhibitory effects of resveratrol treatment. (3) Systemic or spinal administration of resveratrol with morphine significantly blocks microglial activation in the spinal cord and then attenuates the development of acute and chronic morphine tolerance in both male and female mice. CONCLUSION Resveratrol directly suppresses morphine-induced microglial activation through activating AMPK, resulting in significant attenuation of morphine antinociceptive tolerance.
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Affiliation(s)
- Y Han
- Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, China
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Amelioration of behavioural, biochemical, and neurophysiological deficits by combination of monosodium glutamate with resveratrol/alpha-lipoic acid/coenzyme Q10 in rat model of cisplatin-induced peripheral neuropathy. ScientificWorldJournal 2013; 2013:565813. [PMID: 24489506 PMCID: PMC3893013 DOI: 10.1155/2013/565813] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 10/02/2013] [Indexed: 01/24/2023] Open
Abstract
Cisplatin or cis-diamminedichloroplatinum (II) (CDDP) is a cytotoxic chemotherapeutic agent with dose-dependent peripheral neuropathy as a foremost side effect characterised by ataxia, pain, and sensory impairment. Cumulative drug therapy of CDDP is known to produce severe oxidative damage. It mainly targets and accumulates in dorsal root ganglia that in turn cause damage resulting in secondary nerve fibre axonopathy. In the present study, we investigated the neuroprotective effect of the combination of monosodium glutamate (MSG) with three individual antioxidants, that is, resveratrol, alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), in cisplatin (2 mg/kg i.p. twice weekly) induced peripheral neuropathy in rats. After 8 weeks of treatment the degree of neuroprotection was determined by measuring behavioral and electrophysiological properties and sciatic nerve lipid peroxidation, as well as glutathione and catalase levels. The results suggested that pretreatment with the combination of MSG (500 mg/kg/day po) with resveratrol (10 mg/kg/day i.p.) or ALA (20 mg/kg/day i.p.) or CoQ10 (10 mg/kg weekly thrice i.p.) exhibited neuroprotective effect. The maximum neuroprotection of MSG was observed in the combination with resveratrol.
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Bazzo KO, Souto AA, Lopes TG, Zanin RF, Gomez MV, Souza AH, Campos MM. Evidence for the analgesic activity of resveratrol in acute models of nociception in mice. JOURNAL OF NATURAL PRODUCTS 2013; 76:13-21. [PMID: 23273136 DOI: 10.1021/np300529x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The effects of trans-resveratrol (1) were evaluated in acute nociception models induced by capsaicin or glutamate in mice, in an attempt to further characterize its mechanism of action. The oral administration of 1 (50 and 100 mg/kg) reduced significantly the licking behavior elicited by capsaicin (1.6 μg/paw) or glutamate (10 μmol/paw). The co-administration of 1 into the mouse paw (200 μg/site) markedly prevented glutamate-induced licking, without affecting capsaicin responses. In addition, the intrathecal (it) injection of 1 (150 to 600 μg/site) greatly reduced the licking behavior caused by capsaicin, but not glutamate. Similarly, the intracerebroventricular injection of 1 (300 μg/site) caused a potent inhibition of capsaicin-induced nociception, while the glutamate responses remained unaffected. However, the co-administration of 1 (300 μg/site) reduced the biting behavior induced by spinal injection of glutamate (30 μg/site, it), leaving capsaicin (6.4 μg/site)-induced biting unaltered. Notably, the oral administration of 1 (100 mg/kg) inhibited significantly the capsaicin-induced increase of c-Fos and COX-2 labeling in the spinal cord and COX-2 expression in the cortex, but failed to affect c-Fos and COX-2 expression in the glutamate model. This study has explored the effects of 1 in both the capsaicin and glutamate models, extending current knowledge on the analgesic effects of trans-resveratrol.
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Affiliation(s)
- Karen O Bazzo
- Postgraduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil
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Tillu DV, Melemedjian OK, Asiedu MN, Qu N, De Felice M, Dussor G, Price TJ. Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain. Mol Pain 2012; 8:5. [PMID: 22269797 PMCID: PMC3284441 DOI: 10.1186/1744-8069-8-5] [Citation(s) in RCA: 135] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 01/23/2012] [Indexed: 11/10/2022] Open
Abstract
Background Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. Results To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment. Conclusions These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.
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Affiliation(s)
- Dipti V Tillu
- Department of Pharmacology, University of Arizona, 1501 N Campbell Ave, PO BOX 245050, Tucson, AZ 85724, USA
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Utreras E, Terse A, Keller J, Iadarola MJ, Kulkarni AB. Resveratrol inhibits Cdk5 activity through regulation of p35 expression. Mol Pain 2011; 7:49. [PMID: 21736731 PMCID: PMC3212955 DOI: 10.1186/1744-8069-7-49] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Accepted: 07/07/2011] [Indexed: 02/03/2023] Open
Abstract
Background We have previously reported that cyclin-dependent kinase 5 (Cdk5) participates in the regulation of nociceptive signaling. Through activation of the ERK1/2 pathway, Tumor Necrosis Factor-α (TNF-α) induces expression of Egr-1. This results in the sustained and robust expression of p35, a coactivator of Cdk5, in PC12 cells, thereby increasing Cdk5 kinase activity. The aim of our present study was to test whether resveratrol, a polyphenolic compound with known analgesic activity, can regulate Cdk5/p35 activity. Results Here we used a cell-based assay in which a p35 promoter-luciferase construct was stably transfected in PC12 cells. Our studies demonstrate that resveratrol inhibits p35 promoter activity and also blocks the TNF-α mediated increase in Cdk5 activity in PC12 cells. Resveratrol also inhibits p35 expression and blocks the TNF-α mediated increase in Cdk5 activity in DRG neurons. In the presence of resveratrol, the MEK inhibitor decreased p35 promoter activity, whereas the inhibitors of p38 MAPK, JNK and NF-κB increased p35 promoter activity, indicating that these pathways regulate p35 expression differently. The TNF-α-mediated increase in Egr-1 expression was decreased by resveratrol treatment with a concomitant reduction in p35 expression and protein levels, resulting in reduced Cdk5 kinase activity. Conclusions We demonstrate here that resveratrol regulates p35 promoter activity in PC12 cells and DRG neurons. Most importantly, resveratrol blocks the TNF-α-mediated increase in p35 promoter activity, thereby reducing p35 expression and subsequent Cdk5 kinase activity. This new molecular mechanism adds to the known analgesic effects of resveratrol and confirms the need for identifying new analgesics based on their ability to inhibit Cdk5 activity for effective treatment of pain.
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Affiliation(s)
- Elias Utreras
- Functional Genomic Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
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Siddiqui MA, Saquib Q, Ahamed M, Ahmad J, Al-Khedhairy AA, Abou-Tarboush FM, Musarrat J. Effect of Trans-resveratrol on Rotenone-induced Cytotoxicity in Human Breast Adenocarcinoma Cells. Toxicol Int 2011; 18:105-10. [PMID: 21976814 PMCID: PMC3183616 DOI: 10.4103/0971-6580.84261] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Rotenone, a botanical insecticide is known to cause apoptosis in various cell types. Trans-resveratrol, a natural phytophenol present in red grapes and wine, is also well documented for its antioxidant, anti-inflammatory, anti-mutagenic, and anticarcinogenic activities. Therefore, the present investigations were carried out to assess the protective effect of trans-resveratrol against rotenone-induced cell death in human breast adenocarcinoma (MCF-7) cells. MCF-7 cells were exposed with various concentrations of rotenone for 24 h, and the loss in percent cell viability was evaluated by MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and neutral red uptake (NRU) assays. A significant decrease in percent cell viability in MCF-7 cells was observed at 50 μM and above concentrations of rotenone, as compared to untreated control. Furthermore, various concentrations (5, 10, and 25 μM) of trans-resveratrol were used to see its protective role on cell viability in rotenone-induced cell death in MCF-7 cells. Pre- or post- treatment of trans-resveratrol for 24 h was given to the cells. The data exhibited a significant dose dependent increase in the percent cell viability under pre- and post-treatment conditions. However, post-treatment of trans-resveratrol for 24 h after rotenone exposure to the cells was relatively less effective. Overall, the results suggest that trans-resveratrol significantly protects MCF-7 cells from rotenone-induced cell death. This model can be used as an effective and economical alternative to animal models for screening the antioxidant activity of a variety of natural compounds/drugs.
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Affiliation(s)
- M. A. Siddiqui
- A.R. Al-Jeraisy Chair for DNA Research, College of Science, King Saud University, Riyadh, Saudi Arabia
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Q. Saquib
- A.R. Al-Jeraisy Chair for DNA Research, College of Science, King Saud University, Riyadh, Saudi Arabia
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - M. Ahamed
- King Abdullah Institute for Nanotechnology, King Saud University, Riyadh, Saudi Arabia
| | - J. Ahmad
- A.R. Al-Jeraisy Chair for DNA Research, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - A. A. Al-Khedhairy
- A.R. Al-Jeraisy Chair for DNA Research, College of Science, King Saud University, Riyadh, Saudi Arabia
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - F. M. Abou-Tarboush
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - J. Musarrat
- A.R. Al-Jeraisy Chair for DNA Research, College of Science, King Saud University, Riyadh, Saudi Arabia
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
- Department of Microbiology, Faculty of Agricultural Sciences, AMU, Aligarh, India
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Montiel-Ruiz RM, Granados-Soto V, García-Jiménez S, Reyes-García G, Flores-Murrieta FJ, Déciga-Campos M. Synergistic interaction of diclofenac, benfotiamine, and resveratrol in experimental acute pain. Drug Dev Res 2011. [DOI: 10.1002/ddr.20441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Pham-Marcou TA, Beloeil H, Sun X, Gentili M, Yaici D, Benoit G, Benhamou D, Mazoit JX. Antinociceptive effect of resveratrol in carrageenan-evoked hyperalgesia in rats: Prolonged effect related to COX-2 expression impairment. Pain 2008; 140:274-283. [DOI: 10.1016/j.pain.2008.08.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Revised: 08/08/2008] [Accepted: 08/14/2008] [Indexed: 11/15/2022]
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Rocha-González HI, Ambriz-Tututi M, Granados-Soto V. Resveratrol: a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther 2008; 14:234-47. [PMID: 18684235 DOI: 10.1111/j.1755-5949.2008.00045.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.
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Affiliation(s)
- Héctor I Rocha-González
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Sede Sur, México, D.F., Mexico
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El-Alfy AT, Ahmed AA, Fatani AJ, Kader F. Amelioration of the cardiovascular manifestations of the yellow scorpion Leiurus quinquestriatus envenomation in rats by red grape seeds proanthocyanidins. Toxicon 2008; 51:321-33. [DOI: 10.1016/j.toxicon.2007.07.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2007] [Revised: 07/02/2007] [Accepted: 07/03/2007] [Indexed: 10/23/2022]
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Shinohara Y, Toyohira Y, Ueno S, Liu M, Tsutsui M, Yanagihara N. Effects of resveratrol, a grape polyphenol, on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Biochem Pharmacol 2007; 74:1608-18. [PMID: 17888406 DOI: 10.1016/j.bcp.2007.08.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 07/26/2007] [Accepted: 08/14/2007] [Indexed: 11/22/2022]
Abstract
We report the effects of resveratrol, a polyphenol found in the skins of red grapes, on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Resveratrol suppressed catecholamine secretion and (22)Na(+) and (45)Ca(2+) influx induced by acetylcholine, an agonist of nicotinic acetylcholine receptors, in a concentration-dependent manner (IC(50)=20.4, 11.0, and 62.8 microM, respectively). Resveratrol also inhibited catecholamine secretion induced by veratridine, an activator of voltage-dependent Na(+) channels, and 56 mM K(+), an activator of voltage-dependent Ca(2+) channels, at concentrations similar to those for (45)Ca(2+) influx. Resveratrol directly inhibited the current evoked by acetylcholine in Xenopus oocytes expressing alpha3beta4 neuronal nicotinic acetylcholine receptors (IC(50)=25.9 microM). Furthermore, resveratrol (IC(50)=5.32 microM) attenuated (14)C-catecholamine synthesis induced by acetylcholine. The present findings suggest that resveratrol inhibits acetylcholine-induced catecholamine secretion and synthesis through suppressing ion influx in cultured bovine adrenal medullary cells.
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Affiliation(s)
- Yuko Shinohara
- Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
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Vascular large conductance calcium-activated potassium channels: functional role and therapeutic potential. Naunyn Schmiedebergs Arch Pharmacol 2007; 376:145-55. [PMID: 17932654 DOI: 10.1007/s00210-007-0193-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Accepted: 09/19/2007] [Indexed: 12/22/2022]
Abstract
Large-conductance Ca2+-activated K+ channels (BK Ca or maxiK channels) are expressed in different cell types. They play an essential role in the regulation of various cell functions. In particular, BK Ca channels have been extensively studied in vascular smooth muscle cells, where they contribute to the control of vascular tone. They facilitate the feedback regulation against the rise of intracellular Ca2+, membrane depolarization and vasoconstriction. BK Ca channels promote a K+ outward current and lead to membrane hyperpolarization. In endothelial cells expression and function of BK Ca channels play an important role in the regulation of the vascular smooth muscle activity. Endothelial BK Ca channels modulate the biosyntheses and release of various vasoactive modulators and regulate the membrane potential. Because of their regulatory role in vascular tone, endothelial BK Ca channels have been suggested as therapeutic targets for the treatment of cardiovascular diseases. Hypertension, atherosclerosis, and diabetes are associated with altered current amplitude, open probability, and Ca2+-sensing of BK Ca channels. The properties of BK Ca channels and their role in endothelial and vascular smooth muscle cells would address them as potential therapeutic targets. Further studies are necessary to identify the detailed molecular mechanisms of action and to investigate selective BK Ca channels openers as possible therapeutic agents for clinical use.
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Alvira D, Yeste-Velasco M, Folch J, Verdaguer E, Canudas AM, Pallàs M, Camins A. Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 2007; 147:746-56. [PMID: 17583434 DOI: 10.1016/j.neuroscience.2007.04.029] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2007] [Revised: 04/03/2007] [Accepted: 04/17/2007] [Indexed: 12/16/2022]
Abstract
The mechanism involved in neuronal apoptosis is largely unknown. Studies performed on neuronal cell cultures provide information about the pathways which orchestrate the process of neuronal loss and potential drugs for the treatment of neurological disorders. In the present study we select resveratrol, a natural antioxidant, as a potential drug for the treatment of neurodegenerative diseases. We evaluate the neuroprotective effects of resveratrol in two apoptotic models in rat cerebellar granule neurons (CGNs): the inhibition of mitochondrial complex I using 1-methyl-4-phenylpyridinium (MPP(+)) (an in vitro model of Parkinson's disease) and serum potassium withdrawal. We study the role of the mammalian silent information regulator 2 (SIRT1) in the process of neuroprotection mediated by resveratrol. Because recent studies have demonstrated that SIRT1 is involved in cell survival and has antiaging properties, we also measured changes in the expression of this protein after the addition of these two apoptotic stimuli. MPP(+)--induced loss of cell viability and apoptosis in CGNs was prevented by the addition of RESV (1 microM to 100 microM). However, the neuroprotective effects were not mediated by the activation of SIRT1, since sirtinol-an inhibitor of this enzyme--did not attenuate them. Furthermore MPP(+) decreases the protein expression of SIRT1. RESV did not prevent serum potassium withdrawal-induced apoptosis although it did completely attenuate oxidative stress production by these apoptotic stimuli. Furthermore, serum potassium withdrawal increases the expression of SIRT1. Our results indicate that the antiapoptotic effects of RESV in MPP(+) are independent of the stimulation of SIRT1 and depend on its antioxidant properties. Furthermore, because SIRT1 is involved in neuronal survival depending on the apoptotic stimuli, changes in the expression of SIRT1 could be involved in the regulation of the apoptotic route.
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Affiliation(s)
- D Alvira
- Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain
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Kumar A, Kaundal RK, Iyer S, Sharma SS. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci 2007; 80:1236-44. [PMID: 17289084 DOI: 10.1016/j.lfs.2006.12.036] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2006] [Revised: 11/22/2006] [Accepted: 12/20/2006] [Indexed: 12/28/2022]
Abstract
Oxidative stress has been implicated in pathophysiology of diabetic neuropathy. All the pathways responsible for development of diabetic neuropathy are linked to oxidative stress in one way or the other. In the present study, we have targeted oxidative stress in diabetic neuropathy using resveratrol, a potent antioxidant. Eight weeks streptozotocin-diabetic rats developed neuropathy which was evident from significant reduction in motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and increased thermal hyperalgesia. The 2-week treatment with resveratrol (10 and 20 mg/kg, i.p.) started 6 weeks after diabetes induction significantly ameliorated the alterations in MNCV, NBF, and hyperalgesia. Resveratrol also attenuated enhanced levels of malondialdehyde (MDA), peroxynitrite and produced increase in catalase levels in diabetic rats. There was marked reduction in DNA fragmentation observed after resveratrol treatment in diabetic rats as evident from decrease in Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in sciatic nerve sections. Results of the present study suggest the potential of resveratrol in treatment of diabetic neuropathy and its protective effect may be mediated through reduction in oxidative stress and DNA fragmentation.
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Affiliation(s)
- Ashutosh Kumar
- Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab-160062, India
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Wallace CHR, Baczkó I, Jones L, Fercho M, Light PE. Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. Br J Pharmacol 2006; 149:657-65. [PMID: 17016511 PMCID: PMC2014645 DOI: 10.1038/sj.bjp.0706897] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including quercetin, catechin and resveratrol. Inhibition of cardiac voltage-gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective. As polyphenols may also modulate ion channels, and possess structural similarities to several antiarrhythmic VGSC inhibitors, we hypothesised that VGSC inhibition may contribute to cardioprotection by these polyphenols. EXPERIMENTAL APPROACH The whole-cell voltage-clamp technique was used to record peak and late VGSC currents (INa) from recombinant human heart NaV1.5 channels expressed in tsA201 cells. Right ventricular myocytes from rat heart were isolated and single myocytes were field-stimulated. Either calcium transients or contractility were measured using the calcium-sensitive dye Calcium-Green 1AM or video edge detection, respectively. KEY RESULTS The red grape polyphenols quercetin, catechin and resveratrol blocked peak INa with IC50s of 19.4 microM, 76.8 microM and 77.3 microM, respectively. In contrast to lidocaine, resveratrol did not exhibit any frequency-dependence of peak INa block. Late INa induced by the VGSC long QT mutant R1623Q was reduced by resveratrol and quercetin. Resveratrol and quercetin also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 microM and 24.9 microM, respectively. In field-stimulated myocytes, ATXII-induced increases in diastolic calcium were prevented and reversed by resveratrol. ATXII-induced contractile dysfunction was delayed and reduced by resveratrol. CONCLUSIONS AND IMPLICATIONS Our results indicate that several red grape polyphenols inhibit cardiac VGSCs and that this effect may contribute to the documented cardioprotective efficacy of red grape products.
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Affiliation(s)
- C H R Wallace
- Department of Pharmacology, University of Alberta, 9-58 Medical Sciences Building Edmonton, Alberta, Canada
| | - I Baczkó
- Department of Pharmacology, University of Alberta, 9-58 Medical Sciences Building Edmonton, Alberta, Canada
- Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical Center, University of Szeged Szeged, Hungary
| | - L Jones
- Department of Pharmacology, University of Alberta, 9-58 Medical Sciences Building Edmonton, Alberta, Canada
| | - M Fercho
- Department of Pharmacology, University of Alberta, 9-58 Medical Sciences Building Edmonton, Alberta, Canada
| | - P E Light
- Department of Pharmacology, University of Alberta, 9-58 Medical Sciences Building Edmonton, Alberta, Canada
- Author for correspondence:
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Bermúdez-Ocaña DY, Ambriz-Tututi M, Pérez-Severiano F, Granados-Soto V. Pharmacological evidence for the participation of NO-cyclic GMP-PKG-K+ channel pathway in the antiallodynic action of resveratrol. Pharmacol Biochem Behav 2006; 84:535-42. [PMID: 16899286 DOI: 10.1016/j.pbb.2006.06.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Revised: 05/23/2006] [Accepted: 06/30/2006] [Indexed: 11/15/2022]
Abstract
The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG)-K+ channels pathway in the antiallodynic action of resveratrol and YC-1 in spinal nerve injured rats was assessed. Ligation of L5/L6 spinal nerves produced a clear-cut tactile allodynia in the rats. Intrathecal administration of resveratrol (100-600 microg) and 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (0.1-2.7 microg, YC-1, a soluble guanylyl cyclase activator) decreased tactile allodynia induced by ligation of L5/L6 spinal nerves. Intrathecal treatment with NG-L-nitro-arginine methyl ester (10-100 microg, L-NAME, a NO synthase inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (1-10 microg, ODQ, a soluble guanylyl cyclase inhibitor), KT-5823 (5-500 ng, a PKG inhibitor) and iberiotoxin (5-500 ng, a large-conductance Ca2+ -activated K+ channel blocker), but not NG-D-nitro-arginine methyl ester (100 microg, D-NAME, an inactive isomer of L-NAME), glibenclamide (12.5-50 microg, ATP-sensitive K+ channel blocker) or vehicle, significantly diminished resveratrol (300 microg)- and YC-1 (2.7 microg)-induced spinal antiallodynia. These effects were independent of prostaglandin synthesis inhibition as indomethacin did not affect resveratrol-induced antiallodynia. Results suggest that resveratrol and YC-1 could activate the proteins of the NO-cyclic GMP-PKG spinal pathway or large-conductance Ca2+ -activated, but not ATP-sensitive, K+ channels at the spinal cord in order to produce at least part of their antiallodynic effect in this model of neuropathy.
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Affiliation(s)
- Deysi Y Bermúdez-Ocaña
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Sede Sur, México, D.F., Mexico
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Gao ZB, Chen XQ, Hu GY. Inhibition of excitatory synaptic transmission by trans-resveratrol in rat hippocampus. Brain Res 2006; 1111:41-7. [PMID: 16876771 DOI: 10.1016/j.brainres.2006.06.096] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2006] [Revised: 06/20/2006] [Accepted: 06/27/2006] [Indexed: 02/05/2023]
Abstract
The red wine polyphenol trans-resveratrol has been found to exert potent protective actions in a variety of cerebral ischemia models. The neuroprotection by trans-resveratrol thus far is mainly attributed to its intrinsic antioxidant properties. In the present study, the effects of the red wine polyphenol on excitatory synaptic transmission were investigated in the CA1 region of rat hippocampal slices. Perfusion with trans-resveratrol (10-100 microM) caused a concentration-dependent inhibition on the filed excitatory postsynaptic potentials (the field EPSPs) without detectable effect on the presynaptic volleys. The inhibition had a slow onset and was reversible. Trans-resveratrol (30 microM) did not change the ratios of paired-pulse facilitation of the field EPSPs tested at intervals of 20, 40 and 80 ms, nor did it alter the membrane properties of postsynaptic CA1 pyramidal neurons. However, trans-resveratrol (30 microM) significantly suppressed glutamate-induced currents in postsynaptic CA1 pyramidal neurons. In dissociated hippocampal neurons, the IC(50) value of trans-resveratrol in inhibition of glutamate-induced currents was 53.3+/-9.4 microM. Kainite and NMDA receptors were more sensitive to the red wine polyphenol than AMPA receptors. The present study for the first time demonstrates that trans-resveratrol inhibits the postsynaptic glutamate receptors, which probably works in concert with its antioxidant action for ameliorating the brain ischemic injury. The findings also support the future use of trans-resveratrol in the treatment of various neurodegenerative disorders.
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Affiliation(s)
- Zhao-Bing Gao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, PR China
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