RESUMO
RATIONALE: Major depressive disorder (MDD) is one of the most diagnosed mental disorders. Despite this, its pathophysiology remains poorly understood. In this context, basic research aims to unravel the pathophysiological mechanisms of MDD as well as investigate new targets and substances with therapeutic potential. Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane channel considered a sensor for inflammation and oxidative stress. Importantly, both inflammation and oxidative stress have been suggested as participants in the pathophysiology of MDD. However, the potential participation of TRPA1 in depressive disorder remains poorly investigated. OBJECTIVE: To investigate the involvement of the TRPA1 channel in the behavioral changes induced by chronic corticosterone administration (CCA) in male mice. METHODS: Swiss male mice were exposed to 21 days of CCA protocol and then treated with HC-030031 or A-967079, TRPA1 antagonists. Behavioral tests, analyzes of oxidative parameters and TRPA1 immunocontent were performed in the prefrontal cortex (PFC) and hippocampus (HIP). RESULTS: CCA induced despair-like behavior in mice accompanied by an increase in the levels of hydrogen peroxide (H2O2), a TRPA1 agonist, which was reversed by TRPA1 antagonists and ketamine (positive control). In addition, CCA protocol reduced the immunocontent of this channel in the HIP and showed a tendency to increase the TRPA1 protein expression in the PFC. CONCLUSION: Our work suggests that TRPA1 channel appears crucial to mediate the behavioral impairment induced by CCA in male Swiss mice.
Assuntos
Corticosterona , Transtorno Depressivo Maior , Masculino , Animais , Camundongos , Canal de Cátion TRPA1/metabolismo , Peróxido de Hidrogênio/metabolismo , InflamaçãoRESUMO
Chronic pain is a common symptom experienced during cancer progression. Additionally, some patients experience bone pain caused by cancer metastasis, which further complicates the prognosis. Cancer pain is often treated using opioid-based pharmacotherapy, but these drugs possess several adverse effects. Accordingly, new mechanisms for cancer pain management are being explored, including transient receptor potential channels (TRPs). TRP ion channels are expressed in several tissues and play a key role in pain detection, especially TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1). In the present review, we describe the role of TRPV1 and TRPA1 involved in cancer pain mechanisms. Several studies have revealed that the administration of TRPV1 or TRPA1 agonists/antagonists and TRPV1 or TRPA1 knockdown reduced sensitivity to nociception in cancer pain models. TRPV1 was also found to be involved in various models of cancer-induced bone pain (CIBP), with TRPV1 expression reportedly enhanced in some models. These studies have demonstrated the TRPV1 or TRPA1 association with cancer pain in models induced by tumour cell inoculation into the bone cavity, hind paw, mammary fat pad, and sciatic nerve in mice or rats. To date, only resiniferatoxin, a TRPV1 agonist, has been evaluated in clinical trials for cancer pain and showed preliminary positive results. Thus, TRP channels are potential targets for managing cancer-related pain syndromes.
Assuntos
Dor do Câncer/tratamento farmacológico , Dor do Câncer/fisiopatologia , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Ensaios Clínicos como Assunto , Humanos , Manejo da Dor , Canal de Cátion TRPA1/agonistas , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Canais de Potencial de Receptor Transitório/agonistas , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genéticaRESUMO
AIMS: Breast cancer-induced chronic pain is usually treated with opioids, but these compounds cause various adverse effects. Transient receptor potential ankyrin 1 (TRPA1) is involved in cancer pain; also, endogenous TRPA1 agonists are associated with cancer pain development. The aim of this study was to observe the antinociceptive effect of a repeated-dose TRPA1 antagonist administration and the production of endogenous TRPA1 agonists and TRPA1 expression in bone tissue in a model of breast cancer pain in mice. Second, we used a sequence reading archive (SRA) strategy to observe the presence of this channel in the mouse bone and in mouse bone cell lines. MAIN METHODS: We used BALB/c mice for experiments. The animals were subjected to the tumor cell inoculation (4 T1 strain). HC-030031 (a TRPA1 antagonist) treatment was done from day 11 to day 20 after tumor inoculation. TRPA1 expression and biochemical tests of oxidative stress were performed in the bone of mice (femur). SRA strategy was used to detect the TRPA1 presence. KEY FINDINGS: Repeated treatment with the TRPA1 antagonist produced an antinociceptive effect. There was an increase in hydrogen peroxide levels, NADPH oxidase and superoxide dismutase activities, but the expression of TRPA1 in the bone tissue was not altered. SRA did not show TRPA1 residual transcription in the osteoblast and osteoclast cell lines, as well as for mice cranial tissue and in mouse osteoclast precursors. SIGNIFICANCE: The TRPA1 receptor is a potential target for the development of new painkillers for the treatment of bone cancer pain.
Assuntos
Acetanilidas/farmacologia , Osso e Ossos/efeitos dos fármacos , Dor do Câncer/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neoplasias Mamárias Animais/complicações , Nociceptividade/efeitos dos fármacos , Purinas/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores , Acetanilidas/administração & dosagem , Animais , Osso e Ossos/metabolismo , Dor do Câncer/etiologia , Dor do Câncer/metabolismo , Dor do Câncer/patologia , Feminino , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Purinas/administração & dosagemRESUMO
Arachis hypogaea L. (peanut) leaf is traditionally used for the treatment of insomnia in Asia. However, studies describing the safety and toxicity profile for this plant preparation are limited. Thus, the goal of this study was to investigate the toxicity of peanut leaf hydroalcoholic extract (PLHE) repeated treatment. The extract was administered orally (100, 300 or 1000 mg/kg) in male and female Wistar rats for 28 days (OECD guideline 407). PLHE treatment did not cause mortality or weight variation in the animals. Also, there was no alteration on locomotor activity (open field test), motor coordination (rotarod test), or anxiety behaviour (elevated plus-maze test). Male rats had a reduction in relative liver weight (100 mg/kg) and an increase in total kidney weight (1000 mg/kg), but there was no change in biochemical and haematological parameters after PLHE treatment. Free extracellular double-stranded DNA (dsDNA) levels was also evaluated, but PLHE treatment did not increase this parameter in rat organs. Also, the dose of 1000 mg/kg of PLHE significantly increased the total thiols in the liver of females compared with the control animals. Thus, PLHE did not induce toxicity after repeated exposure for 28 days in rats.
Assuntos
Arachis , Extratos Vegetais/toxicidade , Administração Oral , Álcoois/química , Animais , Feminino , Masculino , Folhas de Planta , Ratos Wistar , Solventes/química , Testes de Toxicidade SubagudaRESUMO
Depression is one of the most common mood disorders, which affects one in six people at some point in life. However, the treatment of this disease is still a challenge. Chronic corticosterone administration (CCA) is a widely used animal model to study the mechanisms involved, as well as possible therapeutic strategies for the treatment of depression. Moreover, elevated oxidative stress has been observed in psychiatric disorders, including major depression and, in this context, antioxidant therapy may be a potential therapeutic alternative. In this study, we investigated the effect of seven days of treatment with apocynin, an antioxidant of natural origin, on depressive-like behavior and oxidative parameters in mice submitted to CCA. After 21 days of corticosterone administration (20 mg/Kg/day, subcutaneously, s.c.), we observed the development of depressive-like behavior with an increase in immobility time on tail suspension test and forced swimming test and reduction in total grooming time on splash test. Also, we found high superoxide dismutase activity and hydrogen peroxide levels whereas catalase activity was reduced in the prefrontal cortex, hippocampus and striatum. Seven days of treatment with apocynin (100 mg/Kg/day orally, p.o), performed immediately after corticosterone administration in the last week of protocol, was able to reverse the most of these changes, revealing its antidepressant-like effect. In conclusion, our results suggest apocynin as an antidepressant-like agent with a mechanism of action based on the attenuation of oxidative changes induced by CCA.
Assuntos
Acetofenonas/administração & dosagem , Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Corticosterona/administração & dosagem , Depressão/induzido quimicamente , Depressão/prevenção & controle , Masculino , CamundongosRESUMO
Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients' daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20-30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG35-55) antigen and CFA (complete Freund's adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice.
Assuntos
Encefalomielite Autoimune Experimental/complicações , Hiperalgesia/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neuralgia/fisiopatologia , Nociceptividade/fisiologia , Medula Espinal/fisiopatologia , Canal de Cátion TRPA1/fisiologia , Acetanilidas/farmacologia , Acetanilidas/uso terapêutico , Acetofenonas/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Antipirina/análogos & derivados , Antipirina/farmacologia , Antipirina/uso terapêutico , Dipirona/farmacologia , Dipirona/uso terapêutico , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/toxicidade , NADPH Oxidases/antagonistas & inibidores , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Nociceptividade/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Estresse Oxidativo , Oximas/farmacologia , Oximas/uso terapêutico , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/toxicidade , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/biossíntese , Canal de Cátion TRPA1/genética , Ácido Tióctico/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Breast carcinoma causes severe pain, which decreases the quality of life of patients. Current treatments produce adverse effects and have limited efficacy. Transient potential receptor ankyrin 1 (TRPA1) is related to the onset of cancer and neuropathic pain. The aim of this study was to evaluate the involvement of TRPA1 in a model of breast carcinoma. We injected 4T1 cells in the fourth caudal mammary fat pad of female BALB/c mice, and after 20 days we observed mechanical and cold allodynia and spontaneous nociception behavior (mouse grimace scale detection, MGS). TRPA1 selective antagonist (HC-030031 or A-967079) administration or intrathecal administration of TRPA1 antisense (AS) oligonucleotide was performed. The activity of NADPH oxidase, superoxide dismutase (SOD) and hydrogen peroxide (H2O2) levels were evaluated. The chemical hyperalgesia produced by a TRPA1 agonist (allyl isothiocyanate, AITC) was also detected. The administration of TRPA1 antagonists, TRPA1 AS, or antioxidant, transiently attenuated MGS, or mechanical and cold allodynia. Intraplantar injection of AITC also caused nociception. NADPH oxidase or SOD activity and H2O2 levels were increased in the sciatic nerve and hind paw skin samples. The 4T1 cells did not express TRPA1, and the use of HC-030031 or α-lipoic acid did not reduce the cytotoxic effect of a chemotherapeutic drug (paclitaxel). Thus, TRPA1 could be investigated as a target for breast carcinoma pain treatment.
Assuntos
Dor do Câncer , Neoplasias Mamárias Experimentais , Canal de Cátion TRPA1 , Acetanilidas/farmacologia , Acetanilidas/uso terapêutico , Analgésicos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Dor do Câncer/genética , Dor do Câncer/metabolismo , Linhagem Celular Tumoral , Feminino , Peróxido de Hidrogênio/metabolismo , Hiperalgesia/tratamento farmacológico , Neoplasias Mamárias Experimentais/complicações , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Endogâmicos BALB C , NADPH Oxidases/metabolismo , Nociceptividade/efeitos dos fármacos , Oximas/uso terapêutico , Paclitaxel/farmacologia , Purinas/farmacologia , Purinas/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Pele/metabolismo , Superóxido Dismutase/metabolismo , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/genética , Ácido Tióctico/uso terapêuticoRESUMO
Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Dacarbazina/toxicidade , Hiperalgesia/induzido quimicamente , Melanoma Experimental , Canal de Cátion TRPA1/efeitos dos fármacos , Animais , Células HEK293 , Humanos , Hiperalgesia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Canal de Cátion TRPA1/metabolismoRESUMO
Copaifera officinalis L. possesses traditional uses as an analgesic, anti-inflammatory, and antiseptic. However, until now the antinociceptive effect and the mechanism of action were not described for Copaifera officinalis L. oil and no compound present in this oil was identified to be responsible for its biological effects. The goal of this study was to identify the presence of kaurenoic acid in Copaifera officinalis oil and investigate its antinociceptive effect, mechanism of action, and possible adverse effects in mice. The quantification of kaurenoic acid in Copaifera officinalis oil was done by HPLC-DAD technique. Male and female albino Swiss mice (25-35 g) were used to test the antinociceptive effect of Copaifera officinalis (10 mg/kg, intragastric) or kaurenoic acid (1 mg/kg) in the tail-flick test, intraplantar injection of capsaicin, allyl isothiocyanate (AITC) or complete Freund's adjuvant (CFA). Copaifera officinalis oil and kaurenoic acid caused the antinociceptive effect in the tail-flick test in a dose-dependent manner, and their effect was reversed by naloxone (an opioid antagonist). Copaifera officinalis oil or kaurenoic acid reduced the nociception caused by capsaicin or AITC and produced an anti-allodynic effect in the CFA model (after acute or repeated administration for 7 days). Possible adverse effects were also observed, and non-detectable adverse effect was observed for the intragastric administration of Copaiba officinalis oil or kaurenoic acid and in the same way, the treatments were neither genotoxic nor mutagenic at the doses tested. Thus, Copaiba officinalis oil, and kaurenoic acid possess antinociceptive action without adverse effects.
Assuntos
Analgésicos/farmacologia , Diterpenos/farmacologia , Fabaceae/química , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Capsaicina/farmacologia , Feminino , Adjuvante de Freund/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Camundongos , Medição da Dor/métodosRESUMO
Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.
Assuntos
Neoplasias Mamárias Animais/patologia , Nociceptividade , Acetaminofen/farmacologia , Acetaminofen/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Neoplasias Ósseas/sangue , Neoplasias Ósseas/secundário , Cálcio/sangue , Canabinoides/agonistas , Linhagem Celular Tumoral , Codeína/farmacologia , Codeína/uso terapêutico , Modelos Animais de Doenças , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Locomoção , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/fisiopatologia , Camundongos Endogâmicos BALB C , Morfina/farmacologia , Morfina/uso terapêutico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Naproxeno/farmacologia , Naproxeno/uso terapêutico , Medição da DorRESUMO
Diosmetin is an Omethylated flavone found naturally in citrus fruit, and it was identified in Amphilophium crucigerum (L.), a plant popularly used as an analgesic. This compound had different pharmacological effects and presented a chemical structure like the flavonoid eriodyctiol that exhibited antinociceptive effects by TRPV1 antagonism. However, the possible antinociceptive effect of this compound was not well documented. Thus, the goal of the present study was to evaluate the antinociceptive effect of diosmetin and its mechanism of action. The diosmetin effect on different pain models and its possible adverse effects were assessed on adult Swiss male mice (25-30â¯g). Mice spinal cord samples were used on calcium influx and binding assays using TRPV1 agonists. First, it was observed that the diosmetin reduced calcium influx mediated by capsaicin in synaptosomes and displace the specific binding to [3H]-resiniferatoxin in membrane fractions from the spinal cord of mice. Diosmetin (0.15 to 1.5â¯mg/kg, intragastric, i.g.) presented antinociceptive and antiedematogenic effect in the capsaicin intraplantar test and induced antinociception in a noxious heat test (48⯰C). Also, treatment with diosmetin reduced mechanical and heat hypersensitivity observed in a model of inflammatory or neuropathic pain. Acute diosmetin administration in mice did not induce locomotor or body temperature changes, or cause liver enzyme abnormalities or alter renal function. Moreover, there were no observed changes in gastrointestinal transit or induction of ulcerogenic activity after diosmetin administration. In conclusion, our results support the antinociceptive properties of diosmetin which seems to occur via TRPV1 antagonist in mice.
Assuntos
Analgésicos/farmacologia , Flavonoides/farmacologia , Neuralgia/tratamento farmacológico , Dor/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/administração & dosagem , Analgésicos/toxicidade , Animais , Cálcio/metabolismo , Capsaicina/farmacologia , Modelos Animais de Doenças , Diterpenos/metabolismo , Relação Dose-Resposta a Droga , Flavonoides/administração & dosagem , Flavonoides/toxicidade , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Neuralgia/fisiopatologia , Dor/fisiopatologia , Medição da Dor , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Testes de ToxicidadeRESUMO
There is a major, unmet need for the treatment of cancer pain, and new targets and medicines are required. The transient receptor potential ankyrin 1 (TRPA1), a cation channel expressed by nociceptors, is activated by oxidizing substances to mediate pain-like responses in models of inflammatory and neuropathic pain. As cancer is known to increase oxidative stress, the role of TRPA1 was evaluated in a mouse model of cancer pain. Fourteen days after injection of B16-F10 murine melanoma cells into the plantar region of the right hind paw, C57BL/6 mice exhibited mechanical and thermal allodynia and thigmotaxis behavior. While heat allodynia was partially reduced in TRP vanilloid 1 (TRPV1)-deficient mice, thigmotaxis behavior and mechanical and cold allodynia were absent in TRPA1-deficient mice. Deletion of TRPA1 or TRPV1 did not affect cancer growth. Intrathecal TRPA1 antisense oligonucleotides and two different TRPA1 antagonists (HC-030031 or A967079) transiently attenuated thigmotaxis behavior and mechanical and cold allodynia. A TRPV1 antagonist (capsazepine) attenuated solely heat allodynia. NADPH oxidase activity and hydrogen peroxide levels were increased in hind paw skin 14 days after cancer cell inoculation. The antioxidant, α-lipoic acid, attenuated mechanical and cold allodynia and thigmotaxis behavior, but not heat allodynia. Whereas TRPV1, via an oxidative stress-independent pathway, contributes partially to heat hypersensitivity, oxidative stress-dependent activation of TRPA1 plays a key role in mediating thigmotaxis behavior and mechanical and cold allodynia in a cancer pain model. TRPA1 antagonists might be beneficial in the treatment of cancer pain.
Assuntos
Dor do Câncer/metabolismo , Melanoma Experimental , Canal de Cátion TRPA1/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Thermal injury promotes tissue inflammation and pain, which is difficult to control. Different peripheral mechanisms seem to be involved in burn pain, such as free radical-induced damage, but further study is still needed to understand how oxidant substances induced nociceptor sensitization. The transient receptor potential ankyrin 1 (TRPA1) is an ion channel activated by oxidants substances, and it could be sensitized after tissue inflammation. This study evaluated the TRPA1 involvement in nociception and inflammation produced by a thermal injury model. Male Wistar rats were used. The concentration of the TRPA1 antagonist (HC-030031, 0.05%) on base cream was chosen using allyl isothiocyanate intraplantar test. Then, the base cream containing HC-030031 was tested on the thermal injury model (induced by warm water immersion of hind paw, under anesthesia), and silver sulfadiazine (1%) was used as a positive control. Cream treatments on the hind paw were done daily (200â¯mg/paw) for 6â¯days after thermal injury. Also, nociception (static and dynamic mechanical allodynia, heat allodynia, and spontaneous pain) or edema were evaluated. On day 6, inflammatory and oxidative parameters were assessed. The base cream containing HC-030031 produced antinociceptive and anti-inflammatory effects (reduced the edema and inflammatory cells infiltration) and decreased the levels of hydrogen peroxide, or superoxide dismutase and NADPH oxidase activities after thermal injury. Thus, this study showed the involvement of the TRPA1 receptor in the nociception and inflammation caused by thermal injury and suggested that TRPA1 antagonists might be useful as novel treatments for pain and inflammation by topical application.
Assuntos
Acetanilidas/administração & dosagem , Analgésicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Queimaduras/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Purinas/administração & dosagem , Canal de Cátion TRPA1/antagonistas & inibidores , Administração Tópica , Animais , Modelos Animais de Doenças , Masculino , Nociceptividade/efeitos dos fármacos , Ratos WistarRESUMO
BACKGROUND AND AIMS: Cardiovascular diseases of thrombotic origin are related to high mortality and standard therapeutic agent used in this case is acetylsalicylic acid (ASA), but serious adverse events may occur. However, recent data has suggested the plant Campomanesia xanthocarpa has antiplatelet activity and could be a viable alternative. In this study we investigated the effects of the encapsulated powder of this plant in human platelet aggregation. METHODS: 23 healthy subjects were randomly divided into three groups: (1) ASA (100mg), (2) C. xanthocarpa (1000mg) or (3) synergism (500mg of C. xanthocarpa plush 50mg of ASA); daily for five days. Antiplatelet activity was determined by turbidimetric method using ADP or arachidonic acid (AA) agonists before, 5 and 8days after treatments. RESULTS: Treatment with C. xanthocarpa and synergism caused a reduction of 8±13.5% and 12.5±5% in platelet aggregation induced by ADP after 5days of treatment, respectively, returning to basal levels after 8days. For AA agonist, 5days of treatment with C. xanthocarpa, ASA or synergism caused a reduction of 46±15%, 36±12% and 69.3±6% in platelet aggregation, respectively, and first two groups returned to baseline values 8days after treatment ended. Synergism group prolonged antiplatelet effect maintaining aggregation reduction after 8days the end of treatment. CONCLUSION: C. xanthocarpa showed antiplatelet action when stimulated by agonist AA, and contributed to the antiplatelet effect when associated with ASA for both agonists, allowing dose reduction to 50mg.
Assuntos
Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Myrtaceae , Extratos Vegetais/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Adulto , Aspirina/farmacologia , Plaquetas/citologia , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Myrtaceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Adulto JovemRESUMO
BACKGROUND: Complex hemostatic mechanisms are involved in the pathophysiology of various diseases, including cardiovascular diseases. Among them, dysregulation of platelet activity is linked to the progression of atherosclerosis and mainly involves platelet aggregation and a decrease in blood flow in the vascular endothelium. The major platelet activation pathways mediated by agonists involve the arachidonic acid pathway, adenosine diphosphate pathway, serotonin pathway, nitric oxide pathway, and action of free radicals on molecules involved in platelet aggregation. These mechanisms have been widely studied and discussed because they are inhibited by the use of medicinal plants in complementary and alternative medicine, thus reducing platelet aggregation. RESULTS: Of the main plants discussed in this review, which have antiplatelet activity, some include saffron, garlic, green tea, St. John's wort, ginger, ginkgo biloba, ginseng, and guavirova. These herbal medicines have phytochemical components, which are directly related to the antiplatelet activity of the plant, such as flavonoids, curcumins, catechins, terpenoids, polyphenols, and saponins. While the majority of the medicinal plants mentioned here were native to the Asian continents, some are distributed worldwide, and found to a smaller extent throughout the American continent, European continent, Mediterranean, African continent, and the Middle East. CONCLUSION: This review showed that several plants and/or compounds exhibit anti-platelet activity, and are therefore potential research targets for developing drugs to treat diseases related to aggregation disorders.
Assuntos
Produtos Biológicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Plantas Medicinais/química , Inibidores da Agregação Plaquetária/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doenças Cardiovasculares/metabolismo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/isolamento & purificaçãoRESUMO
BACKGROUND: Atherosclerosis is an inflammatory disease that affects the arterial wall leading to myocardial, cerebral, and peripheral ischemic syndromes. The use of low doses of aspirin inhibits platelet aggregation and inflammation and prevents cardiovascular mortality. However, ASA may produce hemorrhagic events. Thus, several studies have sought new natural compounds to suppress platelet aggregation without causing serious adverse effects. PURPOSE: In this sense, this study aims to compare the effects of Campomanesia xanthocarpa plant extract with those of acetylsalicylic acid (ASA) on inflammatory parameters observed in homozygous mice knockout for the low-density lipoprotein receptor (LDLr-KO) treated with a hypercholesterolemic diet. MATERIAL AND METHODS: In this study, 28 male LDLr-KO mice were divided into three groups and fed a hypercholesterolemic diet for 4 weeks. Thereafter, the animals that received the hypercholesterolemic diet were treated for 5 days with (1) distilled water, (2) C. xanthocarpa extract, or (3) acetylsalicylic acid. The levels of inflammatory markers were assessed in the blood samples. The gastric tolerability of the animals after oral administration of the treatments was assessed through quantification of the lesions in the gastric mucosa. RESULTS: The levels of proinflammatory cytokines IL-1, IL-6, TNF-α, and INF-γ were reduced to 19.2 ± 3%, 20.4 + 1.3%, 24.7 ± 1.2%, and 20.8 ± 1.7%, respectively, in the group treated with C. xanthocarpa, when compared to control group. Furthermore, treatment with plant extract significantly increased the levels of the anti-inflammatory cytokine IL-10 by 27.3 ± 5.9%, but ASA showed no significant effect on the same cytokines when compared to the control group, with the exception of IL-10, which presented an increase of 8.6 ± 3.5%. Treatments with C. xanthocarpa and ASA also caused significant reductions of 26.4 ± 3% and 38.4± 6% in the serum levels of oxLDL, respectively. However, only treatment with C. xanthocarpa reduced the levels of anti-oxLDL antibodies when compared with the control (25.8 ± 6%). In addition, the analyzed extract did not induce ulcerogenic activity, while ASA induced the formation of lesions. CONCLUSION: In conclusion, treatment with C. xanthocarpa causes anti-inflammatory activity in hypercholesterolemic animals, with results superior to those obtained with the use of ASA.
Assuntos
Aspirina/uso terapêutico , Aterosclerose/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Aspirina/farmacologia , Brasil , Lipoproteínas LDL/sangue , Lipoproteínas LDL/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Myrtaceae/química , Estresse Oxidativo/efeitos dos fármacos , Plantas Medicinais/químicaRESUMO
Cardiovascular diseases (CVD) are considered the leading cause of morbidity and mortality from chronic diseases in the world. In addition, about 20% of first and recurrent acute myocardial infarctions (MI) are silent. In this context, subclinical atherosclerosis culminates in evident CVD, through the evolution of early risk factors such as hypercholesterolemia, hypertriglyceridemia and others. The main problem in CVD is related to the long-time between the start of the subclinical atherosclerosis and the manifestation of the disease. The identification of subjects at risk of such events is obviously substantial, since identification leads to implementation and compliance with effective preventive measures that reduce such risk. In this sense, this review demonstrates biomarkers as an alternative to early detection of subclinical atherosclerosis. One of the proposed biomarkers is the Ischemia-modified albumin (IMA), being considered a promising biochemical biomarker for atherosclerotic conditions. Another marker that is gaining strength and is associated with the IMA are the advanced oxidation protein products (AOPP), its measurement provides information on the level of exposure to potentially harmful changes to proteins and metabolic control. And last but not least we have nitric oxide as an early marker mainly related to endothelial dysfunction. In this review also is evidenced the use of the Campomanesia xanthocarpa, a plant native to southern region from Brazil extensively used as complementary and alternative medicine, and natural products to reduce protein oxidation and improve the availability of nitric oxide and consequently vascular function, reducing the risk for development of CVD.