RESUMO
BACKGROUND: Vanillosmopsis arborea Baker has recognized economic value owing to the high content of (-)-α-bisabolol (BISA) in the essential oil of its stem (EOVA). The antinociceptive effect of EVOA has already been demonstrated, and ß-cyclodextrin (ßCD) is known to improve the analgesic effect of various substances. PURPOSE: Thus, we aimed to evaluate the orofacial antinociceptive effect of a complex containing EOVA-ßCD in rodents. METHODS: EOVA was obtained by simple hydrodistillation, and the essential oil was complexed with ßCD. The animals (nâ¯=â¯6/group) were treated orally with EOVA-ßCD (10 or 50â¯mg/kg), or vehicle (control), and subjected to cutaneous orofacial nociception (formalin, capsaicin, acidic saline or glutamate), corneal (hypertonic saline) or temporomandibular (formalin) tests. The expression of FOS protein was analyzed in the spinal cord. Molecular docking was performed using the 5-HT3 and M2 receptors and BISA. RESULTS: The oral administration of EOVA-ßCD reduced nociceptive behaviour. Moreover, EOVA-ßCD decreased FOS expression. The molecular docking study indicates that BISA interacts with 5-HT3 and M2 receptors, indicating the potential mechanism of action of the tested compound. CONCLUSIONS: Our results indicate that EOVA-ßCD possesses orofacial antinociceptive effect, indicating that this complex can be used in analgesic drug development.
Assuntos
Analgésicos/uso terapêutico , Dor Facial/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/uso terapêutico , Extratos Vegetais/uso terapêutico , Sesquiterpenos/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Analgésicos/química , Analgésicos/farmacologia , Animais , Asteraceae/química , Masculino , Sesquiterpenos Monocíclicos , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Caules de Planta/química , Roedores , Sesquiterpenos/química , Sesquiterpenos/farmacologia , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologiaRESUMO
BACKGROUND: Skeletal muscle inflammation is strongly associated with pain and may impair regeneration and functional recovery after injury. Since anti-inflammatory and antinociceptive effects have been described for the inclusion complex of carvacrol and ß-cyclodextrin (ßCD-carvacrol), this study investigated the effects of ßCD-carvacrol in a model of acute skeletal muscle inflammation. METHODS: Muscle injury was induced in male Wistar rats by injection of 3% carrageenan in the gastrocnemius muscle. Rats were orally pretreated with saline (vehicle) or ßCD-carvacrol (20, 40, 80 and 180 mg/kg) one hour before administration of carrageenan. RESULTS: The injection of carrageenan in the gastrocnemius muscle increased tissue myeloperoxidase (MPO) activity (p < 0.001), edema (p < 0.001) and the levels of tumoral necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, macrophage inflammatory protein (MIP-2), but not IL-10 levels. Also, it increased mechanical hyperalgesia and decreased the grip force of animals. Pretreatment with ßCD-carvacrol (80 or 160 mg/kg) significantly decreased muscle MPO activity and edema 24 h after injury in comparison to vehicle-pretreated group. Animals pretreated with ßCD-carvacrol (160 mg/kg) presented significantly lower levels of IL-1ß, IL-6 and MIP-2 and higher levels of IL-10 six hours after induction and lower levels of TNF-α and MIP-2 after 24 h when compared to the vehicle group. Pretreatment with ßCD-carvacrol also reduced mechanical hyperalgesia and limited the decrease of grip force (80 or 160 mg/kg; p < 0.001) 6 and 24 h after injury. CONCLUSION: These results show that ßCD-carvacrol reduces inflammation and nociception in a model of acute injury to skeletal muscles.
Assuntos
Mediadores da Inflamação/metabolismo , Monoterpenos/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Nociceptividade/efeitos dos fármacos , beta-Ciclodextrinas/administração & dosagem , Animais , Carragenina/toxicidade , Cimenos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Força da Mão/fisiologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Nociceptividade/fisiologia , Ratos , Ratos WistarRESUMO
Cyclodextrins (CDs) have been widely used as a promising alternative in the formation of inclusion complexes with poorly soluble molecules. From this perspective, the present study aimed to study the inclusion complexes of diosmin in ß-cyclodextrin, chemically quantify the diosmin-in-gel preparation and analyze the stability of the gels. Furthermore, we evaluated the effect of therapeutic pulsed ultrasound (TPU) in association with the gel-diosmin complex on the parameters of muscle damage and oxidative stress in rats. Serum creatine kinase (CK) levels were used as an indicator of skeletal muscle injury. Lipid peroxidation (thiobarbituric acid-reactive substances [TBARS]) and superoxide dismutase and catalase activities were used as indicators of oxidative stress. The results obtained indicated that the inclusion complex obtained by co-evaporation had the highest complexation efficiency and stability; there was no change in the features of diosmin on incorporation into the Carbopol gel. Additionally, a significant (p <0.05) decrease was observed in CK levels (TPU plus gel-diosmin: 178.4 ± 85.3 U/L) relative to the untreated group (527.8 ± 46.1 U/L). Levels of TBARS were lower in the TPU plus gel-diosmin group (0.008 ± 0.0004 nmol malondialdehyde/mg protein, p <0.05) compared with the untreated group (0.081 ± 0.011 nmol malondialdehyde/mg protein, p <0.05, n = 6). Catalase activity did not statistically significantly differ between the treatment groups, and superoxide dismutase activity was lower in the diosmin-treated group (0.320 ± 0.11 U/mg protein) compared with the untreated group (0.983 ± 0.40 U/mg protein). These results suggest that TPU in association with the diosmin-gel complex is effective in reducing muscle damage and oxidative stress after mechanical trauma.
Assuntos
Diosmina/farmacologia , Músculo Esquelético/diagnóstico por imagem , Estresse Oxidativo , Terapia por Ultrassom , Ondas Ultrassônicas , Animais , Géis , Masculino , Modelos Animais , Músculo Esquelético/metabolismo , Ratos , Ratos WistarRESUMO
Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in ß-cyclodextrin (LIM-ßCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-ßCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-ßCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-ßCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with ßCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options.
Assuntos
Analgésicos/uso terapêutico , Cicloexenos/uso terapêutico , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Medula Espinal/efeitos dos fármacos , Terpenos/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Animais , Capsaicina/toxicidade , Modelos Animais de Doenças , Combinação de Medicamentos , Interações Medicamentosas , GABAérgicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Limoneno , Masculino , Camundongos , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Dor Musculoesquelética/induzido quimicamente , Nociceptividade/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Medula Espinal/metabolismo , Estatísticas não ParamétricasRESUMO
BACKGROUND: Due to its unclear pathophysiology, the pharmacological treatment of fibromyalgia is a challenge for researchers. Studies using medicinal plants, such as those from the genus Lippia, complexed with cyclodextrins (CDs) have shown innovative results. OBJECTIVE: The present research intended to evaluate the effect of an inclusion complex containing ß-cyclodextrin (ßCD) inclusion complex with Lippia grata (LG) essential oil in a chronic musculoskeletal pain model, its central activity and its possible interaction with neurotransmitters involved in pain. METHODS: After acid saline-induced chronic muscle pain, male mice were evaluated for primary and secondary hyperalgesia and muscle strength. Moreover, an antagonist assay was performed to assess the possible involvement of the opioidergic, serotonergic and noradrenergic pathways. In addition, Fos protein in the spinal cord was assessed, and a docking study and antioxidant assays were performed. RESULTS: The treatment with LG-ßCD, especially in the dose of 24mg/kg, was able to significantly decrease (p<0.05) the paw withdrawal and muscle threshold. Furthermore, LG-ßCD was shown to affect the opioidergic and serotonergic pathways. There were no significant changes in muscle strength. Fos protein immunofluorescence showed a significant decrease in expression in the dorsal horn of the spinal cord. The main compounds of LG showed through the docking study interaction energies with the alpha-adrenergic and µOpioid receptors. In all antioxidant assays, LG exhibited stronger antioxidant activities than LG-ßCD. CONCLUSION: This study suggested that LG-ßCD could be considered as a valuable source for designing new drugs in the treatment of chronic pain, especially musculoskeletal pain.
Assuntos
Antioxidantes/análise , Dor Crônica/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Lippia/química , Simulação de Acoplamento Molecular , Dor Musculoesquelética/tratamento farmacológico , Óleos Voláteis/uso terapêutico , beta-Ciclodextrinas/química , Analgésicos/uso terapêutico , Animais , Dor Crônica/complicações , Modelos Animais de Doenças , Hiperalgesia/complicações , Masculino , Metisergida/uso terapêutico , Camundongos , Dor Musculoesquelética/complicações , Naloxona/uso terapêutico , Folhas de Planta/química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/patologia , Ioimbina/uso terapêuticoRESUMO
Cyclodextrins (CDs) have been used as important pharmaceutical excipients for improve the physicochemical properties of the drugs of low solubility as the essential oil of Hyptis martiusii. This oil is important therapeutically, but the low solubility and bioavailability compromises your use. Therein, the aim of this study was to obtain and to characterize physico-chemically the samples obtained by physical mixture (PM), paste complexation (PC) and slurry complexation (SC) of the essential oil Hyptis martiusii (EOHM) in ß-CD, and to compare the antibacterial and modulatory-antibiotic activity of products obtained and oil free. The physicochemical characterization was performed by differential scanning calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Karl Fischer titration. Additionally, the antibacterial tests were performed by microdilution technique. Thus, it was observed that the PM method showed low complexing capacity, unlike PC and SC in which it was observed the formation of inclusion complexes. In addition, the second stage of the TG/DTG curves showed that SC was the best method inclusion with mass loss of 6.9% over the PC that was 6.0%. The XRD results corroborate with the results above suggesting the formation of new solid phase and the SEM photomicrographs showed the porous surface of the samples PC and SC. The essential oil alone demonstrated an antibacterial and modulatory effect against the S. aureus and the Gram negative strain, respectively. However, the ß-CD and the inclusion complex did not demonstrate any biological activity in the performed antibacterial assays.
Assuntos
Antibacterianos/química , Hyptis/química , Óleos Voláteis/química , beta-Ciclodextrinas/química , Antibacterianos/farmacologia , Varredura Diferencial de Calorimetria/métodos , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Composição de Medicamentos/métodos , Bactérias Gram-Negativas/efeitos dos fármacos , Óleos Voláteis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X/métodos , beta-Ciclodextrinas/farmacologiaRESUMO
Terpenes constitute the largest class of natural products and are important resources for the pharmaceutical, food and cosmetics industries. However, due to their low water solubility and poor bioavailability there has been a search for compounds that could improve their physicochemical properties. Cyclodextrins (natural and derived) have been proposed for this role and have been complexed with different types of terpenes. This complexation has been demonstrated by using analytical techniques for characterizing complexes such as DSC, NMR, XRD, FTIR, and TGA. The formation of inclusion complexes has been able to improve drug characteristics such as bioavailability, solubility and stability; and to enhance biological activity and efficacy. This review shows strong experimental evidence that cyclodextrins improve the pharmacological properties of terpenes, and therefore need to be recognized as being possible targets for clinical use.
Assuntos
Ciclodextrinas/química , Ciclodextrinas/farmacologia , Terpenos/química , Animais , Ciclodextrinas/farmacocinética , Humanos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Remirea maritima has been widely used in the treatment of diarrhea, kidney disease, and high fever and for therapeutic purposes, such as an analgesic and anti-inflammatory. However, few scientific research studies on its medicinal properties have been reported. PURPOSE: The present study aimed to investigate the anticancer potential of aqueous extract (AE), 40% hydroalcoholic extracts (40HA) and 70% (70HA) from R. maritima in experimental models and to identify its phytochemical compounds. METHODS: The chemical composition of AE, 40HA and 70HA was assessed by HPLC-DAD and ESI-IT-MS/MS. In vitro activity was determined on cultured tumor cell, NCI-H385N (Broncho-alveolar carcinoma), OVCAR-8 (Ovarian carcinoma) and PC-3M (prostate carcinoma) by the MTT assay, and the in vivo antitumor activity was assessed in Sarcoma 180-bearing mice. Toxicological parameters were also evaluated as well as the humoral immune response. RESULTS: Among the aqueous and hydroalcoholic extracts of R. maritima, only 40HA showed in vitro biological effect potential, presenting IC50 values of 27.08, 46.62 and >50µg/ml for OVCAR-8, NCI-H385M and PC-3M cells lines, respectively. Regarding chemical composition, a mixture of isovitexin-2''-O-ß-D-glucopyranoside, vitexin-2''-O-ß-D-glucopyranoside, luteolin-7-O-glucuronide and 1-O-(E)-caffeoyl-ß-D-glucose were identified as the major phytochemical compounds of the extracts. In the in vivo study, the tumor inhibition rates were 57.16-62.57% at doses of 25mg/kg and 50mg/kg, respectively, and the tumor morphology presented increasing numbers of apoptotic cells. Additionally, 40HA also demonstrated significantly increased of OVA-specific total Ig. CONCLUSIONS: 40HA exhibited in vitro and in vivo anticancer properties without substantial toxicity that could be associated with its immunostimulating properties.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Cyperaceae/química , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Etanol , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , Solventes , Espectrometria de Massas por Ionização por Electrospray , ÁguaRESUMO
BACKGROUND: Citronellal (CT) is a monoterpene with antinociceptive acute effect. ß-Cyclodextrin (ßCD) has enhanced the analgesic effect of various substances. HYPOTHESIS/PURPOSE: To evaluate the effect of CT both complexed in ß-cyclodextrin (CT-ßCD) and non-complexed, in a chronic muscle pain model (CMP) in mice. STUDY DESIGN: The complex containing CT in ßCD was obtained and characterized in the laboratory. The anti-hyperalgesic effect of CT and CT-ßCD was evaluated in a pre-clinical in vivo study in a murine CMP. METHODS: The complex was characterized through differential scanning calorimetry, derivative thermogravimetry, moisture determination, infrared spectroscopy and scanning electron microscopy. Male Swiss mice were pre-treated with CT (50mg/kg, po), CT-ßCD (50mg/kg, po), vehicle (isotonic saline, po) or standard drug (tramadol4 mg/kg, ip). 60 min after the treatment and then each 1h, the mechanic hyperalgesia was evaluated to obtain the time effect. In addition, the muscle strength using grip strength meter and hyperalgesia were also performed daily, for 7 days. We assessed by immunofluorescence for Fos protein on brains and spinal cords of mice. The involvement of the CT with the glutamatergic system was studied with molecular docking. RESULTS: All characterization methods showed the CT-ßCD complexation. CT-induced anti-hyperalgesic effect lasted until 6h (p <0.001) while CT-ßCD lasted until 8h (p <0.001vs vehicle and p <0.001vs CT from the 6th h). CT-ßCD reduced mechanical hyperalgesia on all days of treatment (p <0.05), without changing muscle strength. Periaqueductal gray (p <0.01) and rostroventromedular area (p <0.05) showed significant increase in the Fos protein expression while in the spinal cord, there was a reduction (p <0.001). CT showed favorable energy binding (-5.6 and -6.1) to GluR2-S1S2J protein based in the docking score function. CONCLUSION: We can suggest that ßCD improved the anti-hyperalgesic effect of CT, and that effect seems to involve the descending pain-inhibitory mechanisms, with a possible interaction of the glutamate receptors, which are considered as promising molecules for the management of chronic pain such as CMP.
Assuntos
Aldeídos/química , Aldeídos/farmacologia , Analgésicos/farmacologia , Dor Crônica/prevenção & controle , Cymbopogon/química , Hiperalgesia/prevenção & controle , Monoterpenos/química , Monoterpenos/farmacologia , Mialgia/prevenção & controle , Óleos Voláteis/química , Óleos Voláteis/farmacologia , beta-Ciclodextrinas/química , Monoterpenos Acíclicos , Animais , Química Encefálica/efeitos dos fármacos , Força da Mão , Masculino , Camundongos , Simulação de Acoplamento Molecular , Força Muscular/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
This study aimed to evaluate the orofacial antinociceptive effect of the Cymbopogon winterianus essential oil (LEO) complexed in ß-cyclodextrin (LEO-CD) and to assess the possible involvement of the central nervous system (CNS). The LEO was extracted, chromatographed, and complexed in ß-cyclodextrin. The complex was characterized by differential scanning calorimetry (DSC) and thermogravimetry derivative (TG/DTG). Male Swiss mice (2-3 months) were treated with LEO-CD (50-200 mg/kg, p.o.), vehicle (distilled water, p.o.), or standard drug (i.p.) and subjected to the orofacial nociception formalin-, capsaicin-, and glutamate-induced. After the formalin test, the animals were perfused and the brains subjected to immunofluorescence for Fos. The rota-rod test (7 rpm/min) was carried out. Geraniol (37.57%) was the main compound of LEO. DSC and TG/DTG proved the complexation. The orofacial nociceptive behavior was significantly (p < 0.05) reduced. The number of Fos-positive cells was significantly changed in the dorsal raphe nucleus (p < 0.01), locus coeruleus (p < 0.001), trigeminal nucleus (p < 0.05), and trigeminal thalamic tract (p < 0.05). LEO-CD did not cause changes in motor coordination in the rota-rod test. Thus, our results suggested that LEO-CD has an orofacial antinociceptive profile, probably mediated by the activation of the CNS without changing the motor coordination.
RESUMO
Remirea maritima is a tropical plant with a reticulated root system belonging to the family Cyperaceae, also known to have biologically active secondary metabolites. However, very few data on R. maritima's biological actions are available and there are no reports regarding the redox-active profile of this plant. In this study, we examined the total phenolic content of Remirea maritima hydroalcoholic (RMHA) extracts, redox properties against different reactive species generated in vitro and their cytotoxic effect against fibroblasts (L929) and melanoma (B16F10) cells. Total reactive antioxidant potential index (TRAP) and total antioxidant reactivity (TAR) results revealed that RMHA at all concentrations tested showed significant antioxidant capacity. RMHA was also effective against hydroxyl radical formation, reduction of Fe3+ to Fe2+ and in scavenging nitric oxide (NO) radicals. In vitro, the level of lipid peroxidation was reduced by RMHA extract and the data showed significant oxidative damage protection. The RMHA cytotoxicity was evaluated by a neutral red assay in fibroblast (L929) and melanome (B16F10) cells. The obtained results showed that the RMHA (40 and 80 µg/mL, respectively) reduced 70% of the viable cells. In conclusion, this study represents the first report regarding the antioxidant and anti-proliferative potential of R. maritima against B16F10 melanoma cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cyperaceae/química , Fibroblastos/efeitos dos fármacos , Melanoma Experimental/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Fibroblastos/citologia , Fibroblastos/metabolismo , Melanoma Experimental/patologia , Camundongos , OxirreduçãoRESUMO
The analgesic activity of (-)-linalool (LIN), a monoterpene present in essential oils of Lamiaceae species, has been previously demonstrated in rodents. However, its possible use in the treatment of fibromyalgia (FM) was never demonstrated. Additionally, as a short half-life is a limitation for the LIN medicinal application, the employment of drug delivery systems has been used to improve pharmaceutical properties of this compound. We investigated the anti-nociceptive effect of LIN, isolated or in ß-cyclodextrin complex (LIN-CD), in an animal model of chronic non-inflammatory muscle pain (a FM animal model), as well as its effect on the central nervous system (CNS). Male Swiss mice were subjected to two injections of acidic saline (pH 4; 20 µL/gastrocnemius) and were treated on alternate days, with LIN-CD (25 mg/kg, p.o.), LIN (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.), or vehicle (neutral saline). After 60 min, they were screened for mechanical hyperalgesia (von Frey), motor coordination (rotarod), and muscle strength (grip strength meter) for 27 days. The CNS areas involved in the anti-hyperalgesic activity were evaluated by immunofluorescence. LIN or LIN-CD produced a significant reduction (p < 0.001) of mechanical hyperalgesia on chronic non-inflammatory muscle pain model, which remained for 24 h only in LIN-CD, and these compounds significantly (p < 0.05) activated neurons of the locus coeruleus, nucleus raphe magnus, and periaqueductal gray areas. So, our results suggest that LIN-CD improved analgesic profile of LIN, with a probable involvement of descending pain pathways and the anti-nociceptive effect of linalool in an animal model of chronic non-inflammatory muscle pain. So far, only the investigations in animal models of inflammatory pain and supraspinatus were published.
Assuntos
Modelos Animais de Doenças , Fibromialgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Monoterpenos/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/biossíntese , beta-Ciclodextrinas/administração & dosagem , Monoterpenos Acíclicos , Animais , Quimioterapia Combinada , Fibromialgia/metabolismo , Regulação da Expressão Gênica , Hiperalgesia/metabolismo , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodosRESUMO
O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. ß-Cyclodextrin (ß-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in ß-CD (LEO/ß-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/ß-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-ßCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with ß-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia.
Assuntos
Analgésicos/uso terapêutico , Fibromialgia/tratamento farmacológico , Monoterpenos/uso terapêutico , Ocimum basilicum/química , Óleos Voláteis/uso terapêutico , Proteínas Proto-Oncogênicas c-fos/genética , beta-Ciclodextrinas/química , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Fibromialgia/genética , Fibromialgia/fisiopatologia , Força da Mão , Hiperalgesia/tratamento farmacológico , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Monoterpenos/administração & dosagem , Monoterpenos/química , Monoterpenos/isolamento & purificação , Atividade Motora/efeitos dos fármacos , Óleos Voláteis/administração & dosagem , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Folhas de Planta/química , Regulação para Cima/efeitos dos fármacosRESUMO
The treatment of orofacial pain remains a major challenge for modern medicine. Thus, we prepared and physicochemically characterized a new ß-cyclodextrin complex containing Lippia grata leaf essential oil (ß-CD/EO) to investigate their possible antinociceptive activity in animal models of orofacial pain. The results of Differential scanning calorimeter (DSC) and Thermogravimetry/derivative thermogravimetry (TG/DTG) showed that the products prepared by Slurry complexation (SC) method were able to incorporate greater amounts of EO. In the X-ray diffractogram, it was shown that complex between EO and ß-CD was formed. Male Swiss mice were pre-treated with ß-CD/EO (6, 12 or 24 mg/kg, per os, gavage, p.o.), morphine (5 mg/kg, i.p.) or vehicle (distilled water, p.o.) 1 hr before treatment with formalin (20 µL, 2%), capsaicin (20 µL, 2.5 µg) or glutamate (40 µL, 25 µM) into the right upper lip. Our results demonstrated that p.o. treatment with ß-CD/EO was significantly (p < 0.05 or p < 0.001) capable of reducing the nociceptive face-rubbing behaviour in both phases of the formalin test. ß-CD/EO-treated mice were also significantly (p < 0.05 or p < 0.001) protected against nociception induced by capsaicin and glutamate. For the action in the central nervous system (CNS), ninety minutes after the treatment, the mice were perfused, the brains collected, crioprotected, cut in a criostate and submitted to an immunofluorescence protocol for Fos protein. The immunofluorescence protocol demonstrated that the ß-CD/EO significantly activated (p < 0.05; p < 0.01 or p < 0.001) the motor cortex, the Locus ceruleus, the nucleus raphe magnus and the periaqueductal gray of the CNS. These effects apparently did not alter, in tested doses, the motor coordination of mice in the rota-rod test. Our results proposed that ß-CD/EO might present an important draft of drug to the study of new compounds for the treatment of orofacial pain.
Assuntos
Dor Facial/tratamento farmacológico , Lippia/química , Óleos Voláteis/farmacologia , Folhas de Planta/química , beta-Ciclodextrinas/farmacologia , Animais , Capsaicina/farmacologia , Formaldeído/farmacologia , Ácido Glutâmico/farmacologia , Masculino , Camundongos , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Óleos Voláteis/análise , Medição da Dor/métodos , Substância Cinzenta Periaquedutal/efeitos dos fármacosRESUMO
Many plants produce (-)-linalool, a plant-derived monoterpene alcohol, including members of the Lamiaceae (mints) and Lauraceae family (laurels, cinnamon, rosewood). The anti-inflammatory and analgesic effects of (-)-linalool have been widely suggested for various studies. Poor chemical stability and short half-life restrain the clinical applications of some essential oil and monoterpenes, including (-)-linalool. However, ß-cyclodextrin (ß-CD) has been used to increase solubility and stability of lipophilic compounds and also to improve the pharmacological effects. In this study, the antinociceptive effect of (-)-linalool and (-)-linalool/ß-CD was examined using the acetic acid writhing reflex, formalin and hotplate tests in rodents. (-)-Linalool and (-)-linalool/ß-CD demonstrated strong antinociceptive activity in all the chemical- and heat-induced mice models (p < 0.01 or p < 0.001). These findings imply the involvement of both peripheral and central antinociceptive mechanisms. In peritonitis induced by carrageenan, isolated monoterpene or ß-CD complex also reduced total leucocyte migration and TNF-α levels in peritoneal fluid. The inclusion complexes, (-)-linalool/ß-CD, revealed that the antinociceptive effect was significantly (p < 0.01) improved when compared with (-)-linalool alone. Such results were unlikely to be provoked by any motor abnormality. Together, our results suggest that ß-CD might represent an important tool for improvement of analgesic and anti-inflammatory profiles of (-)-linalool and other water-insoluble compounds, such as lipophilic monoterpenes or essential oils.