Evidence for the Analgesic Activity of Resveratrol ... - ACS Publications

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Evidence for the Analgesic Activity of Resveratrol in Acute Models of Nociception in Mice Karen O. Bazzo,† André A. Souto,‡ Tiago G. Lopes,§ Rafael F. Zanin,⊥ Marcus V. Gomez,∥ Alessandra H. Souza,⊥,∇ and Maria M. Campos*,†,⊥,# †

Postgraduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil School of Chemistry, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil § Department of Pathology, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil ∥ Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil ⊥ Institute of Toxicology and Pharmacology, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil ∇ School of Pharmacy, ULBRA, Canoas, RS, Brazil # School of Dentistry, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil ‡

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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cation channels that serve as receptors for noxious heat and vanilloids, such as capsaicin. This class of receptors is associated with central hypersensivity and molecular alterations at the transcriptional and translational levels.8 The activation of both NMDA and TRPV1 receptors is deemed to be involved in central and peripheral mechanisms of acute pain. trans-Resveratrol (1) is a stilbenoid phenolic compound, found in a wide variety of plant species, being abundantly present in the seeds and skin of grapes. Compound 1 has been reported to have multiple biological activities such as anti-

ain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.1−3 This sensation is a major health problem that substantially reduces the quality of life and imparts high health costs and considerable economic loss to society. It usually starts with the activation of the nociceptor sensory receptors, which convey nociceptive information to the central nervous system (CNS). Nociceptor activation involves many pathways and mediators, such as glutamate, which is a pivotal neurotransmitter released in the CNS.4 Glutamate is responsible for major central alterations that occur in acute pain, mainly by activating ionotropic N-methyl-D-aspartate (NDMA) receptors.5−7 TRPV1 receptors are nonselective © 2012 American Chemical Society and American Society of Pharmacognosy

Received: August 1, 2012 Published: December 28, 2012 13

dx.doi.org/10.1021/np300529x | J. Nat. Prod. 2013, 76, 13−21

Journal of Natural Products

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demonstrated that oral administration of 1 is able to significantly reduce capsaicin-induced spontaneous nociception, at doses of 50 and 100 mg/kg (29 ± 11% and 36 ± 10%, respectively) (Figure 1A). Furthermore, oral treatment with 1 (100 mg/kg) also produced a significant reduction of nociceptive behavior elicited by glutamate (39 ± 9%) (Figure 1B). The investigation of effective molecules for management of pain represents a very attractive field of research.19 A few studies have reported analgesic effects for 1 in animal models of diabetic neuropathy or in formalin and carrageenan tests, although its mechanisms of action remain to be determined.20−22 Our group has shown that oral treatment with 1 is able to produce a significant reduction of paw licking caused by capsaicin or glutamate, without clear dose-related effects. A previous study demonstrated the absence of clear dose-related effects for 1, in an experimental model of Parkinson’s disease in rats.23 Furthermore, it has been proposed that 1 generates hormetic bell-shaped dose−response curves in some biological assays, which may support the absence of dose-related effects for 1 in the present study.24 Nevertheless, a recent investigation demonstrated a potent analgesic effect for 1 at a dose of 100 mg/kg, po, in the capsaicin test, confirming our findings,25 although there are no previous studies that have demonstrated the effects of 1 in glutamate-induced nociception. Intraplantar Injection of trans-Resveratrol (1) Reduces Nociception Induced by Glutamate but Not by Capsaicin. Next, it was decided to investigate whether 1 might be effective on capsaicin- or glutamate-induced nociception, when dosed by other routes of administration. In this experimental set, 1 was co-injected with capsaicin or glutamate into the mouse hind paw. The results demonstrated

inflammatory and antiaging, antioxidant, antiatherosclerotic, and antitumor effects.9−14 Only a few studies have investigated the antinociceptive activities of 1. For instance, significant antinociceptive effects have been demonstrated for 1 in the inflammatory hyperalgesia induced by carrageenan in rats.15 Of note, it was demonstrated that the antinociceptive activity of 1 can be reversed by the opioid antagonist naloxone.16 Animal models of acute pain, employing the administration of irritant agents such as capsaicin and glutamate, have been used frequently to study nociception mechanisms. Drug discovery and development continue to be a challenge, and new approaches for pain management are required urgently.17,18 Following this rationale, in the present study, the effects of 1 have been evaluated, for the first time, in two acute models of spontaneous nociception, as induced by capsaicin and glutamate in mice, in order to determine the possible sites of action of trans-resveratrol (1) as well as some of the mechanisms implicated in its effects.

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RESULTS AND DISCUSSION Oral trans-Resveratrol (1) Reduces Nociception Induced by Intraplantar Injection of Capsaicin or Glutamate. The first series of experiments conducted

Figure 1. Effects of oral (panels A and B) or intraplantar (ipl; panels C and D) treatment with trans-resveratrol (1) on spontaneous nociception induced by capsaicin (panels A and C) or glutamate (panels B and D). Each column represents the mean of eight animals, and the vertical lines show the SEM. *Denotes the significance levels in comparison to control values: *p < 0.05. 14



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Figure 2. Effects of intrathecal (it, panels A and B) or intracerebroventricular (icv; panels C and D) treatment with trans-resveratrol (1) on spontaneous nociception induced by capsaicin (panels A and C) or glutamate (panels B and D). Effects of spinal co-administration of 1 (panels E and F) on the biting behavior elicited by the it injection of capsaicin (panel E) or glutamate (panel F). Each column represents the mean of eight animals, and the vertical lines show the SEM. *Denotes the significance levels in comparison to control values: *p < 0.05; **p < 0.01.

that intraplantar (ipl) administration of 1, at a dose of 200 μg/ site, was able to reduce glutamate-induced spontaneous nociception (Figure 1D) (p < 0.05; 33 ± 9%), although it failed to affect capsaicin-induced nociception significantly (Figure 1C). This dose of 1 was selected on the basis of previous studies,26 and it was found active in the formalin test. It might be surmised that 1 acts via different pathways on capsaicin- and glutamate-mediated pain reactions. Data on the capsaicin model allows the suggestion to be made that 1 does not act peripherally in relation to TRPV1 activation. Otherwise, it is feasible that 1 might interfere with peripheral glutamate receptors, namely, NMDA. In a previous study conducted in rats, it was demonstrated that peripheral antinociceptive effects of 1 in the formalin model are related probably to the opening of large and small conductance Ca2+-activated K+ channels, but not ATP-sensitive K+ channels.26 Recently, it was demonstrated that preparations of 1 for local use may be useful clinically to

control postoperative pain, and this action could be explained by its peripheral inhibitory effects on MAP-kinase ERK and mTOR pathways, via AMPK activation.27 Intrathecal trans-Resveratrol (1) Reduces Nociception Induced by Capsaicin but Not by Glutamate. When injected by the intrathecal (it) route, 1 reversed significantly the nociception induced by capsaicin, at doses of 150, 300, or 600 μg per site (p < 0.05), with percentages of inhibition of 33 ± 8%, 44 ± 14%, and 36 ± 12%, respectively (Figure 2A). Again, the effects of 1 were not visibly dose-dependent. On the other hand, the administration of 1 (300 μg/site, it) did not elicit any significant alteration of glutamate-induced licking (Figure 2B). This is suggestive of a central antinociceptive action for 1 in the capsaicin model. Some studies on chronic nociception have suggested that 1 may activate the NO−cyclic GMP−PKG pathway or large-conductance Ca2+-activated, but not ATPsensitive K+ channels, at the spinal cord, restoring altered NOS 15



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Figure 3. Semiquantitative immunohistochemistry analysis for c-Fos after capsaicin injection into the mouse paw in the spinal cord (panel A) or the brain cortex (panel B). Effects of oral treatment with trans-resveratrol (1) on c-Fos positive immunolabeling. Each column represents the mean of four animals, and the vertical lines show the SEM. *Denotes the significance levels in comparison to control values: *p < 0.05. #Denotes the significance levels in comparison to capsaicin-treated animals: #p < 0.05. Representative images for the different experimental groups (panel C) of the spinal cord (lanes a to d) or the cortex (lanes e to h).

behavior (Figure 2F) (p < 0.05, 74 ± 8%), whereas it was not effective in changing capsaicin-induced biting (Figure 2E). In the CNS, 1 is known to inhibit Na+ currents in the dorsal root ganglion neurons.31 It may be hypothesized that 1 exerts suppression or antagonism on the kinetics of Na+ currents, affecting the excitability of the dorsal root neurons and consequently glutamate-induced biting. It was demonstrated recently that it injection of guanosine, a guanine-based purine, inhibited the nociceptive response induced by spinal injection of glutamate, although it failed to affect the capsaicin-mediated biting response in mice,32 as shown herein for 1. It is possible that 1 is able to interfere with the signaling pathways activated by glutamate in the spinal cord, following the activation of either ionotropic or metabotropic receptors. In contrast, 1 failed to alter significantly the biting behavior elicited by it injection of capsaicin, when administered concurrently at the spinal level. The site of injection of capsaicin, or even its concentration, may directly influence the open and closed TRPV1 channel states, probably via PKC-mediated phosphorylation, and thus be responsible for the differences in the effects of 1 as observed in the present study.33,34 Analysis of c-Fos and COX-2 Following Intraplantar Injection of Capsaicin or Glutamate: Systemic Effects of trans-Resveratrol (1). Nociceptive stimuli modulate several

activity and expression, leading to a reduction of allodynia in neuropathic rats.28 Intracerebroventricular trans-Resveratrol (1) Inhibits Nociception Induced by Capsaicin but Not by Glutamate. The intracerebroventricular (icv) administration of 1 displayed a marked inhibition of capsaicin-induced spontaneous nociception (Figure 2C) (p < 0.01; 87 ± 2%), without affecting glutamate-induced nociception (Figure 2D). To the best of our knowledge, there has been only one prior study showing the effects of 1 when injected by the icv route, in the radiant heat tail-flick latency time test. 29 Furthermore, a previous publication has reported that icv administration of 1 displayed antidiabetic actions in mice.30 Nevertheless, this series of experiments reinforces the previous hypothesis that 1 probably interferes with pain transmission via the central TRPV1 receptors. Intrathecal trans-Resveratrol (1) Reduces Biting Nociception Induced by the Spinal Injection of Glutamate but Not of Capsaicin. To investigate further the analgesic effects of 1, the biting behavior evoked by the it injection of glutamate or capsaicin was evaluated by application of these agents into the subdural space of the L5−L6 spinal segments. In this experimental paradigm, the it co-injection of 1 was found to be able to greatly reduce glutamate-induced biting 16



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Figure 4. Semiquantitative immunohistochemistry analysis for c-Fos after glutamate injection into the mouse paw in the spinal cord (panel A) or the brain cortex (panel B). Effects of oral treatment with trans-resveratrol (1) on c-Fos positive immunolabeling. Each column represents the mean of four animals, and the vertical lines show the SEM. *Denotes the significance levels in comparison to control values: *p < 0.05. Representative images for the different experimental groups (panel C) of the spinal cord (lanes a to d) or the cortex (lanes e to h).

to affect glutamate-induced c-Fos activation at both anatomical sites. The administration of 1 (100 mg/kg, per os, po) resulted in a significant diminution of COX-2 expression at the L3−L6 spinal segments (Figure 5A) and also in cerebral cortex sections from capsaicin-injected mice (p < 0.05) (Figure 5B; representative images Figure 5C, panels a to h), according to an assessment using immunohistochemistry. In particular, Western blotting experiments confirmed these results, revealing that 1, dosed orally, is able to modulate the increase of COX-2 expression in the brain cortex, when capsaicin was injected into the mouse paw (Figure 5D; representative images Figure 5E, panels a to d). Conversely, the oral treatment with 1 (100 mg/ kg) did not interfere with COX-2 immunopositivity allied to the ipl injection of glutamate, in either the spinal cord (Figure 6A) or the cortex brain sections (Figure 6B). The representative images for this series of experiments are depicted in Figure 6C, panels a to h. COX-2 is responsible for the elevated production of prostanoids at the inflammatory sites,39 and 1 has been found to be effective at blocking both the expression and the activity of COX-2.21 The analgesic activity of 1 seems to be related to various pathways of pain control. COX-2 inhibition and K+ channel opening have been suggested as the main underlying mechanisms.40 It has been shown previously that intraprostatic injection of capsaicin resulted in increased central expression of COX-2.41 Interestingly, the oral administration of 1 to mice was able to reduce significantly

pathways and influence transcriptional and translational levels of many biological systems, including immediate genes, such as c-Fos.35 To investigate whether 1 is able to reduce the expression of c-Fos, an immunohistochemistry analysis of lumbar spinal cord and cortex sections was performed. The oral treatment with 1 (100 mg/kg) caused a significant inhibition of capsaicin-induced increased of c-Fos expression, according to an assessment in L3−L6 spinal segments (Figure 3A) (p < 0.01). Otherwise, 1 was not capable of significantly inhibiting capsaicin-induced increase in c-Fos levels at the brain cortex, although the immunolabeling was virtually reduced in animals treated with 1 (Figure 3B; representative images in Figure 3C, panels a to h). The oral administration of 1 (100 mg/kg) also failed to affect the increase of c-Fos labeling in glutamateinjected mice, either in spinal cord (Figure 4A) or brain sections (Figure 4B). The representative images for these experiments are depicted in Figure 4C, panels a to h. It was demonstrated previously that TRPV1 peripheral activation induced by capsaicin elicits modifications on spinal cord glia in mice,36 resulting in increased c-Fos expression.37 Of note, 1 reduced significantly c-Fos expression induced by capsaicin in the spinal cord, but not in the cortex. It may be suggested that the mechanisms of action of 1 probably involve the modulation of TRPV1 activation in the spinal cord, allied to changes in cFos expression. Previous data have indicated that ipl injection of glutamate induced an elevation of c-Fos levels in the mouse spinal cord.38 Nevertheless, the oral administration of 1 failed 17



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Figure 5. Semiquantitative immunohistochemistry analysis for COX-2 after capsaicin injection into the mouse paw in the spinal cord (panel A) or the brain cortex (panel B). Effects of oral treatment with trans-resveratrol (1) on COX-2 positive immunolabeling. Representative images for the different experimental groups (panel C) of the spinal cord (lanes a to d) or the cortex (lanes e to h). Effects of treatment with trans-resveratrol (1) on COX-2 expression in the brain cortex of capsaicin-injected mice (panel D), as assessed by Western blotting. Representative images for different experimental groups (panel E, lane a: saline/saline; lane b: trans-resveratrol/saline; lane c: saline/capsaicin; lane d: trans-resveratrol/capsaicin). Each column represents the mean of four animals, and the vertical lines show the SEM. *Denotes the significance levels in comparison to control values: *p < 0.05; **p < 0.01. #Denotes the significance levels in comparison to capsaicin-treated animals: #p < 0.05; ##p < 0.01.

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capsaicin-induced COX-2 expression in both the spinal cord and the brain cortex. Thus, 1 might affect COX-2 induction, when nociception involves the activation of TRPV1 receptors by capsaicin. Excitotoxic events lead to increased COX-2 expression, supporting previous results on the increased central levels of COX-2 after glutamate peripheral injection.42 However, systemic treatment with 1 failed to affect the up-regulation of COX-2, according to assessment at the spinal cord or the brain cortex of glutamate-injected mice.

EXPERIMENTAL SECTION

General Experimental Protocols. trans-Resveratrol (1) was purchased from Pharma Nostra (Rio de Janeiro, Brazil; >98% purity). Capsaicin and glutamate were from Sigma-Aldrich (St. Louis, MO, USA). All other chemicals were from standard commercial suppliers and were of analytical grade quality. Animals. All animal care and experimental procedures were in accordance with the current guidelines of the National Institutes of Health (NIH). Animal experiments were approved by the local Animal Ethics Committee (protocol number: 10/00175). The number of animals and intensities of noxious stimuli used were the minimum necessary to demonstrate consistent effects of drug treatments. Male 18



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Figure 6. Semiquantitative immunohistochemistry analysis for COX-2 after glutamate injection into the mouse paw in the spinal cord (panel A) or the brain cortex (panel B). Effects of oral treatment with trans-resveratrol (1) on COX-2 positive immunolabeling. Each column represents the mean of four animals, and the vertical lines show the SEM. Representative images for the different experimental groups (panel C) of the spinal cord (lanes a to d) or the cortex (lanes e to h). μL) into the right hindpaw. Mice were observed individually for 15 min after glutamate injection, and the amount of time spent in licking the injected paw (in s) was considered as indicative of nociception. Glutamate- or Capsaicin-Induced Biting. This series of experiments was aimed to investigate further the possible central effects of 1. For this purpose, the methodology described previously was used.45 Briefly, animals received an it injection containing glutamate (30 μg in 5 μL) or capsaicin (6.4 μg in 5 μL) into the subdural space of the L5−L6 spinal segments. The biting behavior was defined as a single head movement directed at the flanks or hind limbs, resulting in contact with the animal’s snout.46 Compound 1 was coinjected with glutamate or capsaicin, by the it route (300 μg in 5 μL). Immunohistochemistry Studies. The expression of c-Fos and COX-2, which are known biochemical markers of nociception and inflammation, respectively, was measured by immunohistochemistry, as described by Pereira et al.47 The spinal cords and the brains were excised rapidly 60 min after capsaicin or glutamate application and fixed in buffered neutral formalin. For these experiments, 1 was dosed by the oral route, at 100 mg/kg. Sections were mounted onto gelatincoated slides. Rabbit polyclonal antibodies raised against c-Fos and COX-2 (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA, USA) were diluted in Tris-buffered saline containing 0.3% Triton X-100, 2% donkey serum, and 1% BSA, and the sections were incubated overnight at room temperature, before being incubated for 2 h with biotinylated donkey anti-rabbit antibody (1:1000; Amersham Pharmacia Biotech Europe, Freiburg, Germany), for 2 h with avidin−biotin peroxidase complex (1:1000; Vectastain ABC kit, Vector Laboratories, Burlingame, CA, USA), and finally visualized with diaminobenzidine via the nickel-enhanced glucose-oxidase

Swiss mice (30 to 35 g, n = 4 to 8 per group), obtained from Universidade Federal de Pelotas (UFPEL, Brazil), were used. The animals were kept on a 12 h light/dark cycle (light on at 7 A.M.) at 22 ± 1 °C and housed in plastic cages (six per cage) with filtered water and commercial food ad libitum under controlled humidity (60−70%) and temperature (22 ± 2 °C). In all experiments, the animals were acclimatized to the laboratory for at least 1 h before use. Drug Administration Protocols. Thirty minutes before the experimental sessions, the animals were placed individually in observation chambers. After this adaptation period, the administration of 1 was conducted as follows: by the oral route (po) (50−200 mg/ kg), intraplantarly (ipl) (200 μg/paw), intrathecally (it) (150−600 μg/ site, in 5 μL), or by the intracerebroventricular route (icv) (300 μg/ site, in 5 μL). Compound 1 was co-injected or administered 30 min (oral route) or 10 min (it and icv) before nociception induction. Control groups received saline solution at the same schedules of treatment. The doses and intervals of drug administration were selected on the basis of published data or pilot experiments.26,29 Capsaicin-Induced Nociception. The method used for capsaicininduced licking was similar to that previously described.43 Following the appropriate intervals of time after administration of 1, 20 μL of capsaicin (1.6 μg per paw) was injected under the plantar surface of the right hindpaw (ipl). Animals were observed individually for 5 min for the time spent licking the injected paw (in s), which was considered as indicative of nociception. Glutamate-Induced Nociception. The procedure adopted in the present study was similar to a previously described study.44 The animals were pretreated with 1 at the suitable time intervals and received an ipl injection of glutamate solution (10 μmol per paw, 20 19



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method. The procedure also included negative controls with the omission of the primary antibody, which did not show any immunoreaction. The images were captured using a digital camera (DS-5 M-L1, Nikon, NY, USA) connected to an optical microscope (Nikon Eclipse 50i) and analyzed through the Image NIH Image J 1.36b software. The number of c-Fos and COX-2 positive cells was quantified and expressed as the positive area per field.48 For this series of experiments, four animals per group were used. Western Blotting Analysis. The expression of COX-2 was evaluated additionally by Western blot. For this purpose, the method described before was used with minor modifications.49,50 The animals were pretreated with 1 (100 mg/kg) or saline solution by the oral route. The cortexes of capsaicin (1.6 μg/paw)-injected mice were collected and homogenized in hypotonic buffer (HEPES 10 mM, MgCl2 1.5 mM, KCl 10 mM, PMSF 0.5 mM, soybean trypsin inhibitor 1.5 μg/mL, pepstatin A 7 μg/mL, leupeptin 5 μg/mL, benzamidine 0.1 mM, and DTT 0.5 mM). Nonidet P-40 10% was added to the homogenate, and the mixture was cooled in ice and incubated under continuous shaking for 15 min. The proteins (20 μg) were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis on 10% (wt/vol) acrylamide and 0.275% (wt/vol) bisacrylamide gels and electrotransferred onto nitrocellulose membranes. Membranes were incubated in TBS-T [20 mmol/L Tris−HCl, pH 7.5, 137 mmol/L NaCl, 0.05% (v/v) Tween 20] containing 1% (wt/vol) nonfat milk powder for 1 h at room temperature. The membranes were incubated for 12 h with primary antibody against COX-2 (Santa Cruz Biotechnology, dilution range 1:250), rinsed with TBS-T, and exposed to horseradish-peroxidase-linked anti-IgG antibodies for 2 h at room temperature. β-Actin was used to normalize data. Chemiluminescent bands were detected using X-ray films, and densitometry analyses were performed using Image-J software. Statistical Analysis. The results are presented as the means ± standard error mean of eight animals per group in the behavioral experiments. For the immunohistochemistry and Western blotting experiments, four animals per group were used. The percentages of inhibition were calculated as the mean of inhibitions obtained for each individual experiment. Statistical comparison of the data was performed by Student’s t test or one-way analysis of variance (ANOVA) followed by Dunnet’s test or Tukey’s test; p-values less than 0.05 (p < 0.05) are considered significant.

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AUTHOR INFORMATION

Corresponding Author

*Tel: + 55 51 3320 3562. Fax: + 55 51 3320 3626. E-mail: [email protected]; [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank Mr. J. Soares for his excellent technical assistance. K.O.B. is a mastership postgraduate student in Medicine and Health Sciences receiving grants from CAPES ́ (Coordenaçaõ de Aperfeiçoamento de Pessoal de Nivel Superior). A.H.S. is a postdoctoral student receiving financial support from CAPES. This study was financially supported by CAPES-AUX-PE Toxinologia, CNPq, and PUCRS, in addition to a FINEP research grant “Implantaçaõ , Modernizaçaõ e Qualificaçaõ de Estrutura de Pesquisa da PUCRS” (PUCRSINFRA) #01.11.0014-00.

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