Modulation of TRP channels by resveratrol and other stilbenoids
© Yu et al; licensee BioMed Central Ltd. 2013
Received: 4 December 2012
Accepted: 14 February 2013
Published: 15 February 2013
Resveratrol (3,5,4’ - trihydroxy-trans-stilbene), a widely distributed natural stilbenoid, was proposed to account for the unique effects of red wine on life span and health. It has been reported to possess various biological and pharmacological activities, such as anti-oxidant, anti-inflammatory, and anti-carcinogenic effects. Here, using whole-cell patch-clamp techniques and behavioral analyses, we investigated whether resveratrol and other stilbenoids can modulate TRP channels in sensory neurons in vitro, and have analgesic effects in vivo.
We found that resveratrol dose-dependently suppressed the allyl isothiocyanate (AITC)-induced currents (IAITC) in HEK293 cells that express TRPA1, as well as in rat dorsal root ganglion (DRG) neurons. Instead, pinosylvin methyl ether (PME), another derivate of stilbene which has a similar structure to resveratrol, dose-dependently blocked the capsaicin-induced currents (ICAP) in HEK293 cells that express TRPV1 as well as in DRG neurons. Interestingly, resveratrol had no inhibitory effect on the ICAP, and PME had no effect on the IAITC. Otherwise, trans-stilbene showed no any effect on IAITC or ICAP. The concentration response curve of AITC showed that resveratrol inhibited the action of TRPA1 not by changing the EC50, but by suppressing the AITC-induced maximum response. By contrast, the inhibition of TRPV1 by PME did not change the capsaicin-induced maximum response but did cause a right shift of the EC50. Moreover, pre-administration of resveratrol suppressed intraplantar injections of AITC-evoked nocifensive behaviors, as well as that PME suppressed capsaicin-evoked one.
These data suggest that resveratrol and other stilbenoids may have an inhibitory effect on TRP channels. In addition, these stilbenoids modulate TRP channel activity in different ways.
Since the discovery of the Drosophila melanogaster transient receptor potential (trp) gene, it has become known that mammalian genomes contain 28 homologous genes encoding proteins that are capable of forming a large variety of cationic channels, usually with permeability to sodium and calcium . TRPV1 and TRPA1 are members of branch V and A of the TRP family of cation channels respectively, and are expressed by a subset of small-sized DRG or trigeminal ganglia neurons in neonatal rats, adult rats and mice [17, 18]. It is well known that TRPV1 is activated by capsaicin, protons, or heat (with a thermal threshold > 43°C), which cause pain in vivo[17, 19]. Analyses of mice lacking TRPV1 have shown that it is essential for selective modalities of pain sensation, as well as for tissue injury-induced thermal hyperalgesia . Like TRPV1, TRPA1 is activated by various kinds of noxious compounds (such as allyl isothiocyanate (AITC), cinnamaldehyde, cannabinoids, and allicin) through their ability to covalently modify cysteine residues in the channel proteins [21–26]. TRPA1 has also been reported to be activated by bradykinin, intracellular alkalization, and the endogenous aldehyde, 4-hydroxynonenal [21, 27, 28]. Studies using knockout mice demonstrated that TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain . There is no doubt that TRPV1 and TRPA1 are critical molecules for the detection and modulation of pain sensations.
Using patch-clamp and behavior analyses, we investigated the pharmacological effects of resveratrol and related stilbenoids on these two pain-related TRP channels, TRPV1 and TRPA1. We observed that resveratrol significantly inhibited IAITC, but not ICAP, both in heterologous HEK293 cells and DRG neurons. Resveratrol also inhibited AITC-induced nocifensive behavior in adult rats. By contrast, pinosylvin methyl ether (PME), an analog of resveratrol, inhibited ICAP and nocifensive behavior. The pathway targeted by resveratrol and other related stilbenoids may become useful for developing treatments for many painful diseases in the future.
Resveratrol suppresses IAITCbut not ICAPin heterologous HEK293 cells
To examine how resveratrol changes TRPA1 responsiveness, we measured IAITC density by applying a range of concentrations of AITC in the absence or presence resveratrol. We found that treatment with resveratrol (30 μM, 3 min) strongly suppressed IAITC at the maximum response (−115.2 ± 5.9 pA/pF for AITC vs −15.1 ± 1.8 pA/pF for AITC with resveratrol) without affecting EC50 (61.2 μM for AITC vs 61.7 μM for AITC with resveratrol) (Figure 2C). 2-aminoethoxy diphenyl borate (2APB), as a non-electrophilic agonist, is known to activate TRPA1 without covalent modification of the cysteine residues. To further investigate the inhibition mechanism, the effect of resveratrol on 2APB-induced currents in mTRPA1-transfected HEK293 cells was tested. We found that resveratrol also significantly reduced 2APB-induced current in HEK293 cells expressing mTRPA1 (−42.1 ± 14.0 pA/pF for 2APB without resveratrol, n=11; -6.4 ± 2.4 pA/pF for 2APB with resveratrol, n=6, p < 0.05) (Figure 2D, E). We confirmed that application of resveratrol alone at less than 30 μM causes no change of membrane currents in HEK293 cells expressing mTRPA1. These data clearly indicate a suppressive effect of resveratrol on TRPA1 channel activity, and this effect was not dependent on agonist’s electrophilicity. We also tested if resveratrol had any pharmacological actions on another pain-related TRP channel, TRPV1. In contrast to TRPA1, resveratrol at 30 μM did not significantly inhibit ICAP (capsaicin, 20 nM) in HEK293 cells expressing rTRPV1 (Figure 2F, G) (−27.3 ± 7.3 pA/pF for capsaicin without resveratrol, n=6; -27.7 ± 5.4 pA/pF for capsaicin with resveratrol, n=5, p > 0.05).
Resveratrol suppresses IAITCin DRG neurons
PME suppresses ICAPbut not IAITCin heterologous HEK293 cells and DRG neurons
Trans-stilbene showed no modulatory effect on either TRPA1 or TRPV1 channels
Resveratrol/PME reduce the AITC-/capsaicin- induced nocifensive behaviors
TRPA1 and TRPV1 are known to be expressed on sensory neurons and act as an important component of pain. If resveratrol/PME can suppress the TRPA1/TRPV1 activation, pain sensation that is caused through the TRPA1/TRPV1 channels may also be suppressed by resveratrol/PME treatment. To this end, we performed intraplantar injections with AITC or capsaicin to the rat hind paw, and recorded the AITC- or capsaicin-induced nocifensive behaviors, respectively. Consistent with our previous studies, both AITC and capsaicin injections induced a significant flinch behavior of the injected hind paw during the 30 min post-injection period, whereas such behaviors were not observed in vehicle-injected rats (liquid paraffin or saline injection).
Resveratrol has been shown to have chemo-preventive, cardio-protective, anti-aging, anti-oxidative and anti-nociceptive properties . For the first time, we are able to report that resveratrol is a potent inhibitor of TRPA1 in vitro and in vivo. Given that TRPA1 plays important roles in pain transduction and oxidative stress response [28, 33, 34], our observations imply that the reported anti-nociceptive and anti-oxidative properties of resveratrol are possibly the results of the TRPA1 activity inhibition.
In this study, we found that resveratrol could inhibit the IAITC in both heterologous HEK293 cells and DRG neurons in a dose-dependent manner. Two potential mechanisms are suggested to be involved in this inhibitory regulation. One would be that resveratrol inhibits the single channel conductance or open probability. The other would be that resveratrol decreases the channel density of TRPA1 on cell membranes. In the present study, the concentration-response curves of AITC resulting from the effect of resveratrol (Figure 2C) revealed that resveratrol suppressed the maximal response of AITC without conspicuously altering EC50, indicating that resveratrol inhibits TRPA1 activity through a non-competitive (to AITC) mechanism. Resveratrol might inhibit TRPA1 intracellularly by affecting the covalent modification of cysteine residues by AITC in the channel protein and subsequently inhibiting the channel conductance or open probability. However, the lack of effect of resveratrol on the EC50 for AITC-induced currents (Figure 2C), in addition to that resveratrol also suppressed the 2APB-induced currents (Figure 2D, E), indicated that the covalent modification of cysteine residues was not involved in the resveratrol-induced inhibition of TRPA1. Otherwise, resveratrol may decrease the channel density on cell membranes through promoting receptor internalization or by inhibiting membrane insertion of TRPA1 channels. TRPA1 may cycle between the plasma membrane and intracellular compartments, and the balance between membrane insertion and retrieval determines its surface abundance and activity . A recent report indicated that TRPA1 channel desensitization in sensory neurons was regulated by internalization of itself . On the other hand, PME inhibited ICAP. The concentration-response curves of capsaicin resulting from the effect of PME (Figure 4D) revealed that PME increased the EC50 of capsaicin without conspicuously altering maximal response, indicating that the PME inhibition of TRPV1 through a competitive (to capsaicin) mechanism, which differs from the resveratrol inhibition TRPA1. PME may supress the TRPV1 binding affinity for capsaicin, or modify the channel’s responsiveness to its own ligand. Anyway, the detailed mechanisms of resveratrol/PME regulation on TRPA1/TRPV1 requires further study.
In the present study, consistent with the patch-clamp data, topical treatment of resveratrol or PME produced a significantly persistent suppression of the number of paw flinches induced by intraplantar injection of AITC or capsaicin, respectively (Figure 7, 8), indicating resveratrol (or PME) can suppress the TRPA1 (or TRPV1) activity not only in vitro but also in vivo. Resveratrol has been reported to have analgesic properties against acute and chronic pain that is triggered either by nocifensive stimuli, inflammation or nerve injury [9–14]. As TRPA1 and TRPV1 in DRG neurons plays important roles in pain transmission and neurogenic inflammation, our results indicate that inhibition of IAITC by resveratrol, as well as inhibition of ICAP by PME, may at least partly account for its analgesic effects observed in these in vivo studies. These stilbenoids then might be considered as emerging targets for antinociceptive and anti-inflammatory pharmacotherapy.
Resveratrol has been shown to have anti-oxidative, anti-inflammatory, anti-proliferative, anti-angiogenic, and chemo-protective effects, with those on oxidative stress being the most important to human health, and possibly the foundation for some of the other beneficial effects. However, many signaling pathways are among the molecular targets of resveratrol, and thus we cannot be certain exactly what these pathways are at the present time. In concert, these effects may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role . Oxidative stress results from metabolic activity or environmental stimuli, and produces highly reactive chemicals (e.g., H2O2) and oxidizing lipid products (e.g., 4-hydroxynonenal), which are known to activate TRPA1 and subsequently impacts human health [28, 33, 38]. Therefore, our finding that resveratrol inhibits TRPA1 activity may also provide a potential mechanism for the well-known anti-oxidative properties of resveratrol.
Resveratrol, as well as PME, was initially characterized as a phytoalexin, which is an anti-microbial substance synthesized by plants in response to infection . Both of these derivatives of stilbene can inhibit TRP channels. It would be interesting to determine if the basal stilbene structure itself can modulate TRP activity. In the present study, trans-stilbene did not significantly inhibit either TRPA1 or TRPV1 (Figure 6), indicating that the modulation mechanism of these stilbenoids may not result from the direct binding of the basal structure of stilbene with the TRP domain. An indirect mechanism (for example, via the intracellular signals downstream stilbenoids) to explain the modulation of TRP channels by stilbenoids is suggested and needs to be further investigated.
TRPA1 and TRPV1 are widely expressed channel present in many organs and tissues, including the respiratory system, cardiovascular system, gastrointestinal tract, inner ear, skin, skeletal muscle, dental pulp, pancreas, as well as the peripheral and central nervous system. These channels play important roles in inflammation, oxidative stress, and pain signals [40, 41]. In the present study, we demonstrated for the first time that resveratrol and PME can significantly inhibit the TRPA1 and TRPV1 activity in vitro and in vivo, respectively. Therefore, the reported anti-nociceptive activities of resveratrol and PME may be considered to originate from TRP channel inhibition.
Animals and agents
All animal experimental procedures were approved by the Hyogo University of Health Sciences Committee on Animal Research (#2010-22) and were performed in accordance with the National Institutes of Health guidelines on animal care. Adult male Sprague–Dawley (SD) rats (100–250 g; Japan SLC, Inc, Shizuoka, Japan) were used for DRG culture and behavioral studies. Resveratrol (Sigma-Aldrich, St Louis, MO, USA), trans-stilbene (Sigma-Aldrich) and PME (Oy Arbonova Ab, Turku, Finland) were prepared from methanol based stock solutions that had been kept for not longer than 1 month at 4°C. Otherwise, capsaicin was prepared from ethanol based stock solution that was kept at −20°C. All compounds were added from these stock solutions to the recording solution. The final ethanol or methanol concentration in recording solutions was less than 0.1%. AITC was from Nacalai tesque (Kyoto, Japan). 2APB was from Sigma. Glutamax, fetal bovine serum (FBS), Penicillin–Streptomycin, Earle’s balanced salt solution (EBSS, Sigma), DMEM, vitamin solution and OPTI-MEM were from Invitrogen (Carlsbad, CA, USA).
Mammalian cell culture
Human embryonic kidney-derived (HEK293) cells were maintained in DMEM (supplemented with 10% FBS, 2 mM glutamax, Penicillin and Streptomycin) and transfected with 1 μg of a mouse TRPA1 or a rat TRPV1 (mTRPA1 and rTRPV1 respectively) cDNA by using Lipofectamine LTX (Invitrogen). The cDNAs were generous gifts from Dr. Makoto Tominaga. To identify transfected cells, an enhanced green fluorescence protein reporter plasmid (BD Bioscience Clontech, CA) was also transfected at 0.1 μg. For primary culture of DRG neurons, whole DRGs were collected from the adult SD rats (100–150 g) using sterile techniques, and placed in ice-cold EBSS. Adhering fat and connective tissues were removed in order to isolate the DRGs. Each DRG neuron was then immediately placed in a medium consisting of 2ml of EBSS and 1.25 mg/ml of collagenase P (Sigma), and kept at 37°C for 60 min with occasional agitation. After dissociation of the DRG cells, this cell suspension was centrifuged for 5 min at 1000 rpm and the cell pellet was re-suspended in EBSS supplemented with 10% FBS, 2mM Glutamax, Penicillin, Streptomycin and vitamin solution. Recombinant rat nerve growth factor (100 ng/ml, Sigma) was added to the medium.
Whole-cell patch-clamp recordings were performed 2 days after transfection of mTRPA1 cDNA, or 1 day after transfection of rTRPV1 cDNA to HEK293 cells, or 1 day after dissociation of the DRG neurons. Voltage-clamp experiments were performed at -60mV holding potential, and recordings were sampled at 5 kHz and filtered at 2 kHz. Current densities (pA/pF) and normalized currents were measured. The current magnitude was quantified by peak current amplitude in all experiments. A normalized current was obtained from dividing the third application-induced current to the second one, and adopted just in case the magnitude of the second current by agonist was larger than a half of the first current. In experiments with DRG neurons, after AITC was applied, capsaicin (1 μM) was applied at the end of the recording to identify whether IAITC was mediated by TRPA1 channels. Data were obtained in the event that the DRG neurons were sensitive to both AITC and capsaicin applications, since an IAITC in capsaicin-sensitive DRG neurons is certainly a TRPA1-mediated event . The standard bath solution contained 140 mM NaCl, 5mM KCl, 2 mM MgCl2, 2 mM CaCl2, 10 mM HEPES and 10 mM glucose, pH 7.4 (adjusted with NaOH). In some experiment, the calcium-free bath solution contained 140 mM NaCl, 5 mM KCl, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES and 10 mM glucose, pH 7.4 (adjusted with NaOH) was used. The pipette solution contained 140 mM KCl, 5 mM MgATP, 5 mM EGTA and 10 mM HEPES, pH 7.2 (adjusted with KOH). The concentration-response curves for the effect of resveratrol on IAITC densities (pA/pF) or PME on ICAP densities were fit by the Hill equation using KaleidaGraph 4.1 (Synergy Software, PA, USA). All patch-clamp experiments were performed at room temperature (~25°C; RT). The solutions containing drugs were applied to the chamber (1 ml) by a gravity system at a flow rate of 4–5 ml/min.
Twenty-five or twenty-one male adult SD rats (200–250 g) were used for the AITC- or capsaicin-induced nocifensive behavioral analyses, respectively. Behavioral studies were performed in accordance with the procedure of our previous reports [30, 31]. To measure the effect of resveratrol (or PME) on AITC-induced nocifensive behavior, after adaptation, 50 μl resveratrol (300 μM, in saline) or PME (300 μM, in saline) was injected intraplantarly into the rat right hind paw. Five minutes after these injections, rats received intradermal injection of 50 μl of AITC (3% in liquid paraffin) to the same area of resveratrol injected plantar surface. To measure the effect of PME (or resveratrol) on capsaicin-induced nocifensive behavior, after adaptation, 50 μl PME (300 μM, in saline) or resveratrol (300 μM, in saline) was injected in the same manner as above. Five minutes after these injections, rats received intradermal injection of 50 μl of capsaicin (0.05% in saline with 0.5% Tween20). The rats were placed in a wire mesh cage immediately after the AITC or capsaicin injection, and the number of hind paw flinches and duration of licks per 5 min interval during the initial 30 min post-injection period was measured. The total number of flinches and total duration of licks during the entire initial 30 min for AITC or capsaicin was also calculated.
All results are expressed as mean ± SEM. An unpaired t-test or one-way ANOVA was used to compare the electrophysiological data between the groups. One-way or two-way repeated ANOVA followed by Fisher’s PLSD was applied to the behavioral data. A difference was accepted as significant if the probability was less than 5% (p < 0.05).
This work was supported by Grants-in-Aid for Scientific Research KAKENHI 23590730 (YD) and the Research Basis Formation Supporting Project for Private University S0901048 (KN). The authors thank Dr. D. A. Thomas for correcting the English usage on this manuscript.
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