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1.
Addict Biol ; 28(1): e13249, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36577722

RESUMEN

ß-caryophyllene (BCP) is a cannabinoid receptor CB2 agonist plant-derived terpenoid found in different essential oil plants, including rosemary, black pepper, copaiba and cannabis. It has GRAS (generally recognized as safe) status and is approved by the FDA (Food and Drug Administration) for food use. BCP displays agonist activity on the CB2 receptor and is a potential therapeutic target in several neuropsychiatric disorders, including anxiety and drug addiction. Unlike CB1 receptors, activation of the CB2 receptors is devoid of psychotomimetic and addictive properties. In this regard, this study aimed to evaluate the effects of BCP on incentive salience ("wanting") performance and motivational properties elicited by sweetened palatable foods in female Swiss mice. After 9 days of training for incentive salience performance for a sweet reward (hazelnut cream with chocolate), food-restricted mice received a systemic injection of BCP (50 and 100 mg/kg) before testing over 3 days. Moreover, independent groups of female mice were tested on sweet reward-induced conditioned place preference (CPP) for 22 consecutive days. To evaluate BCP effects on the expression of seeking behaviour for sweetened food, mice received a single intraperitoneal injection of BCP (50 mg/kg) 30 min before testing on the CPP task. BCP significantly decreased the incentive performance for a sweet reward compared with the control group in a CB2 receptor-dependent manner. Also, BCP suppressed the expression of sweet reward-CPP. Altogether, these preclinical data demonstrate the potential role of BCP in treating disorders associated with food addiction-like behaviour.


Asunto(s)
Sesquiterpenos , Ratones , Animales , Sesquiterpenos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Motivación , Receptor Cannabinoide CB2 , Receptor Cannabinoide CB1
2.
Braz Oral Res ; 36: e056, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36507743

RESUMEN

The understanding of the biological mechanisms involved in root resorption in deciduous teeth is important to the future development of preventive measures and treatments of this condition. The aim of the present study was to compare the expression and immunostaining of iNOS, MMP-9, OPG and RANKL in the periodontal ligament (PDL) of deciduous teeth with physiologic root resorption (GI), inflammatory pathological root resorption (GII) and permanent teeth (GIII), the negative control. Teeth in GI (n = 10), GII (n = 10) and (GIII) (n = 10) were submitted to immunohistochemical analysis to determine the expression of iNOS, MMP-9, OPG, and RANKL. The immunostaining was analysed by optical density. Statistical analysis included one-way ANOVA, followed by Student-Newman-Keuls post hoc test (p < 0.05). The results showed that iNOS, MMP-9 and RANKL expression in the PDL was higher in GII compared to GI and GIII (p < 0.05). Moreover, RANKL expression was higher in GI compared to GIII (p < 0.001), while OPG immunolabelling was lower in GII compared to GI and GIII (p < 0.001). The PDL of deciduous teeth bearing inflammatory processed exhibited upregulation of resorption-associated factors as well as enzymes related to tissue degradation which, in turn explains the exacerbation and greater susceptibility of those teeth to root resorption process.


Asunto(s)
Ligamento Periodontal , Resorción Radicular , Humanos , Ligamento Periodontal/patología , Resorción Radicular/patología , Metaloproteinasa 9 de la Matriz , Osteoprotegerina , Diente Primario , Ligando RANK , Inflamación/patología
3.
BrJP ; 5(3): 206-212, July-Sept. 2022. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1403663

RESUMEN

ABSTRACT BACKGROUND AND OBJECTIVES: Photobiomodulation (PBM) is an important therapeutic tool for inflammatory process modulation. In this study, the anti-inflammatory and analgesic effect of two different energies and two different wavelengths (660 nm and 830 nm) were investigate and compared through the model of carrageenan-induced paw edema in mice. METHODS: Male Swiss mice, 36 animals (n=6 animals/group) were divided into six groups: Group 1 (saline-control), Group 2 (carrageenan), Group 3 (carrageenan + laser 660 nm, 5.88 J), Group 4 (carrageenan + laser 660 nm, 2.94 J), Group 5 (carrageenan + laser 830 nm, 5.88 J), and Group 6 (carrageenan + laser 830 nm, 2.94 J). PBM was applied 1h after the carrageenan injection which induced paw edema and hyperalgesia, which were measured by means of a plethysmometer and by flicker test using a water bath at 38ºC (±0.5ºC), respectively. Left paws of mice injected with carrageenan exhibited local edema that persisted for up to 6h after its administration. All animals were evaluated before, 1, 2, 3, 4, and 6 h after the injection of carrageenan. RESULTS: PBM, specially the 830 nm wavelength with 2.94 J of energy, reduced the paw edema induced by carrageenan. In addition, the 660 nm wavelengths (5.88 J / 2.94 J) and 830 nm (2.94 J) inhibited thermal hyperalgesia induced by carrageenan after 4 h of paw injection. CONCLUSION: There was evidence that the PBM 830 nm (2.94 J) produced a more pronounced anti-inflammatory effect, while the 660 nm (5.88 J / 2.94 J) energy laser was more effective to inhibit the hyperalgesia response induced by the carrageenan injection.


RESUMO JUSTIFICATIVA E OBJETIVOS: A fotobiomodulação (FBM) é uma importante ferramenta terapêutica para modulação dos processos inflamatórios. Neste estudo, investigou-se o efeito anti-inflamatório e analgésico de duas energias e dois comprimentos de onda diferentes (660 nm e 830 nm) através do modelo de edema de pata induzido por carragenina em camundongos. MÉTODOS: Trinta e seis camundongos Swiss machos (n=6 animais/grupo) foram divididos em seis grupos: Grupo 1 (controle salino), Grupo 2 (carragenina), Grupo 3 (carragenina + laser 660 nm, 5,88 J), Grupo 4 (carragenina + laser 660 nm, 2,94 J), Grupo 5 (carragenina + laser 830 nm, 5,88 J) e Grupo 6 (carragenina + laser 830 nm, 2,94 J). A FBM foi aplicada 1h após a injeção de carragenina que induziu o edema de pata e a hiperalgesia térmica, os quais foram medidos por meio de um pletismômetro e pelo flicker test em banho-maria a 38ºC (±0,5ºC), respectivamente. As patas esquerdas injetadas com carragenina apresentaram edema local que persistiu por até 6h após sua administração. Todos os animais foram avaliados antes, 1, 2, 3, 4, e 6 horas após a injeção de carragenina. RESULTADOS: A FBM, principalmente o comprimento de onda 830 nm com 2,94 J de energia, reduziu o edema de pata induzido pela carragenina. Além disso, o comprimento de onda 660 nm (5,88 J / 2,94 J) e o 830 nm (2,94 J) inibiram a hiperalgesia térmica induzida pela carragenina após 4h da injeção na pata. CONCLUSÃO: Evidenciou-se que a FBM 830 nm (2,94 J) produziu efeito anti-inflamatório mais pronunciado, enquanto o laser de 660 nm (5,88 J / 2,94 J) de energia foi mais eficaz para reduzir a resposta de hiperalgesia induzida pela injeção de carragenina.

4.
Mol Neurobiol ; 59(7): 4436-4452, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35570263

RESUMEN

CTK 01512-2 toxin is a recombinant peptide of the Phα1ß version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512-2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512-2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1-4 h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512-2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512-2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.


Asunto(s)
Dolor Crónico , Venenos de Araña , omega-Conotoxinas , Animales , Bloqueadores de los Canales de Calcio/farmacología , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Hiperalgesia/tratamiento farmacológico , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Venenos de Araña/farmacología , Venenos de Araña/uso terapéutico , omega-Conotoxinas/farmacología , omega-Conotoxinas/uso terapéutico
5.
Int J Biol Macromol ; 194: 402-411, 2022 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-34818530

RESUMEN

The main objective of this study was to investigate the effects of bacterial cellulose hydrogel (BCH) incorporated into montmorillonite (MMT) and its underlying mechanisms of action on a skin wound healing mouse model following pressure injury model. Komagataeibacter hansenii was used to obtain 5 cm in diameter and 0.8 mm of thickness circular bacterial cellulose (BC) sheets, which were incorporated with MMT by deposition ex-site using a 0.1% MMT suspension (100 rpm for 24 h at 28 °C). Afterward, Fourier Transform Infrared Spectroscopy (FT-IR) and Scanning Electron Microscopy (SEM) were used to characterize the bacterial cellulose hydrogel incorporated into montmorillonite (BCH-MMT). The pressure injury model was assessed by macroscopic and histological analysis in male Swiss mice. Both, BC and BCH-MMT, showed a typical FTIR spectrum of cellulosic substrates with pronounces bands around 3344, 2920, 1637, and 1041 cm-1 while microparticles of MMT dispersed uniformly throughout BC were revealed by SEM photographs. Animals treated with BCH-MMT showed significant healing of pressure ulcers as demonstrated by reduced area of redness and spontaneous hyperalgesia, lower amounts of in-site inflammatory cells (to the same level as the positive control Dersani®) and ultimately, complete epidermis re-epithelialization and tissue regeneration. Altogether, these findings suggest that a modified BCH-MMT film could serve as scaffolding for skin tissue engineering and potentially as a novel dressing material for pressure injury.


Asunto(s)
Vendajes , Bentonita , Celulosa , Hidrogeles , Úlcera por Presión , Cicatrización de Heridas , Animales , Masculino , Ratones , Bentonita/uso terapéutico , Celulosa/uso terapéutico , Hidrogeles/uso terapéutico
6.
Neural Regen Res ; 17(2): 450-458, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34269222

RESUMEN

Fibromyalgia (FM) is a complex pathology described as persistent hyperalgesia including somatic and mood dysfunctions, depression and anxiety. Although the etiology of FM is still unknown, a significant decrease in biogenic amines is a common characteristic in its pathogenesis. Here, our main objective was to investigate the role of dopamine D3/D2 receptor during the reserpine-induced pain in mice. Our results showed that pramipexole (PPX) - a dopaminergic D3/D2 receptor agonist - inhibited mechanical allodynia and thermal sensitivity induced by reserpine. Relevantly, PPX treatment decreased immobility time and increased the number of grooming in the forced swimming test and splash test, respectively. Animals that received PPX remained longer in the open arms than the reserpine group using elevated plus-maze apparatus. The repeated PPX administration, given daily for 4 days, significantly blocked the mechanical and thermal allodynia during FM model, similarly to pregabalin, although it failed to affect the reserpine-induced thermal nociception. Reserpine administration induced significant downregulation of dopamine concentration in the central nervous system, and repeated treatment with PPX restored dopamine levels in the frontal cortex and spinal cord tissues. Moreover, PPX treatment inhibited oxidants production such as DCFH (2',7'-dichlorodihydrofluorescein) and nitrite, also decreased oxidative damage (carbonyl), and upregulated the activity of superoxide dismutase in the spinal cord. Together, our findings demonstrated the ability of dopamine D3/D2 receptor-preferring agonist in reducing pain and mood dysfunction allied to FM in mice. All experimental protocols were approved by the Universidade Federal de Santa Catarina (UFSC) Ethics Committee (approval No. 2572210218) on May 10, 2018.

7.
Braz. oral res. (Online) ; 36: e056, 2022. graf
Artículo en Inglés | LILACS-Express | LILACS, BBO - Odontología | ID: biblio-1374757

RESUMEN

Abstract: The understanding of the biological mechanisms involved in root resorption in deciduous teeth is important to the future development of preventive measures and treatments of this condition. The aim of the present study was to compare the expression and immunostaining of iNOS, MMP-9, OPG and RANKL in the periodontal ligament (PDL) of deciduous teeth with physiologic root resorption (GI), inflammatory pathological root resorption (GII) and permanent teeth (GIII), the negative control. Teeth in GI (n = 10), GII (n = 10) and (GIII) (n = 10) were submitted to immunohistochemical analysis to determine the expression of iNOS, MMP-9, OPG, and RANKL. The immunostaining was analysed by optical density. Statistical analysis included one-way ANOVA, followed by Student-Newman-Keuls post hoc test (p < 0.05). The results showed that iNOS, MMP-9 and RANKL expression in the PDL was higher in GII compared to GI and GIII (p < 0.05). Moreover, RANKL expression was higher in GI compared to GIII (p < 0.001), while OPG immunolabelling was lower in GII compared to GI and GIII (p < 0.001). The PDL of deciduous teeth bearing inflammatory processed exhibited upregulation of resorption-associated factors as well as enzymes related to tissue degradation which, in turn explains the exacerbation and greater susceptibility of those teeth to root resorption process.

8.
Phytother Res ; 35(12): 6974-6989, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34709695

RESUMEN

Rosmarinic acid (RA), an ester of caffeic acid and 3, 4-dihydroxyphenyllactic acid, has anti-inflammatory and neuroprotective activities. Herein, this study investigated in silico the drug-likeness and the potential molecular targets to RA. Moreover, it tested the antidepressant-like potential of RA in the lipopolysaccharide (LPS)-induced depression model. RA (MW = 360.31 g/mol) meets the criteria of both Lipinski's rule of five and the Ghose filter. It also attends to relevant pharmacokinetic parameters. Target prediction analysis identified RA's potential targets and biological activities, including the peroxisome proliferator-activated receptor (PPAR) and the cannabinoid receptors CB1 and CB2 . In vivo, RA's acute, repetitive, and therapeutic administration showed antidepressant-like effect since it significantly reduced the immobility time in the tail suspension test and increased grooming time in the splash test. Further, the pretreatment with antagonists of CB1 , CB2 , and PPAR-γ receptors significantly blocked the antidepressant-like effect of RA. Altogether, our findings suggest that cannabinoid receptors/PPAR-γ signaling pathways are involved with the antidepressant-like effect of RA. Moreover, this molecule meets important physicochemical and pharmacokinetic parameters that favor its bioavailability. RA constitutes a promising, innovative, and safe molecule for the pharmacotherapy of major depressive disorder.


Asunto(s)
Antidepresivos , Cinamatos/farmacología , Depsidos/farmacología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , PPAR gamma , Receptores de Cannabinoides , Animales , Antidepresivos/farmacología , Lipopolisacáridos , Transducción de Señal , Ácido Rosmarínico
10.
Life Sci ; 249: 117538, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32169521

RESUMEN

Inflammaging is known as an imbalance between pro-inflammatory and anti-inflammatory immune mechanisms, being related to the onset of neurological disorders, such as major depression and Alzheimer's disease. Considering the known disadvantages regarding the FDA approved drug to manage such illnesses, resveratrol emerges as a natural drug candidate, despite its low bioavailability. In this study, resveratrol analogues were evaluated for their capacity of inhibiting acetylcholinesterase in silico, in vitro, and in vivo. Molecular docking simulations pointed out RSVA1 and RSVA6 as potent inhibitors, even more than resveratrol. Ellman's assay demonstrated RSVA6 as capable of inhibiting 92.4% of the enzyme activity. Further, male Swiss mice were pretreated with RSVA6 (100 mg kg-1) 60 min before receiving scopolamine (1 mg kg-1). The Novel Recognition Object (NOR), Object Location (OLT), and Buried Pellet tests (BPL) demonstrated an RSVA6 neuroprotective effect. In the second round of tests, mice received a single intraperitoneal injection of lipopolysaccharide (0.5 mg kg-1) 24 h before treatment with RSVA6 (1, 10, and 100 mg kg-1). The Open Field (OFT), Tail Suspension (TST), and Splash tests (ST) were evaluated. LPS had no significant effect on the crossing and rearing number, indicating an association between the immobility time and anhedonia observed in the TST and ST, respectively, with depressive-like behavior. RSVA6 significantly reduced the depressive-like behavior triggered by LPS in the TST and ST. Altogether, our data suggest RSVA6 as a potential drug candidate for the treatment of neuroinflammatory conditions.


Asunto(s)
Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Resveratrol/uso terapéutico , Animales , Simulación por Computador , Técnicas In Vitro , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Masculino , Ratones , Simulación del Acoplamiento Molecular , Enfermedades del Sistema Nervioso/inducido químicamente , Resveratrol/análogos & derivados , Escopolamina/administración & dosificación
11.
Int J Mol Sci ; 18(4)2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28368293

RESUMEN

(-)-ß-caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has already been shown in precedent literature to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain. Herein, we endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Furthermore, we sought to demonstrate some of the mechanisms that underlie the modulation BCP exerts on autoimmune activated T cells, the pro-inflammatory scenery of the central nervous system (CNS), and demyelination. Our findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE. In addition, data hereby presented indicates that mechanisms underlying BCP immunomodulatory effect seems to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor. Altogether, our study represents significant implications for clinical research and strongly supports the effectiveness of BCP as a novel molecule to target in the development of effective therapeutic agents for MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental/prevención & control , Inflamación Neurogénica/prevención & control , Parálisis/prevención & control , Receptor Cannabinoide CB2/metabolismo , Sesquiterpenos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Citocinas/metabolismo , Enfermedades Desmielinizantes/prevención & control , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Humanos , Hiperalgesia/prevención & control , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/prevención & control , Inflamación Neurogénica/metabolismo , Inflamación Neurogénica/fisiopatología , Parálisis/metabolismo , Parálisis/fisiopatología , Sesquiterpenos Policíclicos , Receptor Cannabinoide CB2/agonistas , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo
12.
Behav Brain Res ; 320: 365-373, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-27825895

RESUMEN

Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson's disease symptoms and restless legs syndrome. Recently, anti-inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression-like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7days, 1mg/kg, i.p.), but not acute (1h before LPS) treatment with PPX abolished the depression-like behavior induced by LPS (0.1mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1ß levels and reversed LPS-induced increase in its content in mice hippocampus⋅ Repeated PPX treatment also prevented the increase in hippocampal levels of the 3-nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2mg/kg, i.p.) and sulpiride (50mg/kg, i.p.) were unable to prevent the antidepressant-like effect of PPX in LPS-treated mice. Altogether, these results suggest that the observed antidepressant-like effect of PPX in LPS-treated mice may be dependent on its anti-inflammatory properties and may not be related to dopamine D2 receptor activation.


Asunto(s)
Benzotiazoles/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Agonistas de Dopamina/uso terapéutico , Inflamación/complicaciones , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Conducta de Enfermedad/fisiología , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Locomoción/efectos de los fármacos , Malondialdehído/metabolismo , Ratones , Pramipexol , Natación/psicología , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/metabolismo
13.
Mol Neurobiol ; 54(5): 3271-3285, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-27130268

RESUMEN

Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes were blocked by inosine treatment. Additionally, inosine consistently inhibited IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; A2AR: adenosine A2A receptor; IL-17: interleukin-17; IL-4: interleukin-4.


Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/prevención & control , Inosina/uso terapéutico , Receptor de Adenosina A2A/metabolismo , Animales , Ansiedad/complicaciones , Ansiedad/patología , Encefalomielitis Autoinmune Experimental/enzimología , Encefalomielitis Autoinmune Experimental/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Gliosis/metabolismo , Gliosis/patología , Hiperalgesia/complicaciones , Hiperalgesia/patología , Inmunización , Inmunomodulación , Inflamación/complicaciones , Inflamación/patología , Inosina/farmacología , Interleucina-17/biosíntesis , Tejido Linfoide/patología , Ratones Endogámicos C57BL , Modelos Biológicos , Vaina de Mielina/metabolismo , Fosforilación/efectos de los fármacos , Médula Espinal/patología
14.
Mol Neurobiol ; 51(3): 1368-78, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25064055

RESUMEN

Inosine is an endogenous nucleoside that has anti-inflammatory and antinociceptive properties. Inosine is a metabolite of adenosine, and some of its actions suggest the involvement of adenosine A1 receptors (A1Rs). The purpose of this study was to better understand mechanisms of inosine-induced antinociception by investigating the role of A1Rs and purine metabolism inhibitors. Inosine antinociception was evaluated using the formalin test in mice. An A1R-selective antagonist (DPCPX), A1R knockout mice (gene deletion) and mice with A1R reduced expression (antisense oligonucleotides) were used to assess the role of A1Rs in the antinociceptive action of inosine. Binding assays were performed to compare the affinity of inosine and adenosine for A1Rs. Finally, the role of adenosine and inosine breakdown was assessed using deoxycoformycin (DCF) and forodesine (FDS) as enzymatic inhibitors of adenosine deaminase and purine nucleoside phosphorylase, respectively. Inosine induced antinociception in the formalin test when given by systemic, spinal and peripheral routes. Systemically, inosine exhibited a potency similar to adenosine, and its effects were inhibited by DPCPX. Inosine did not induce antinociception in A1R knockout mice or in mice with reduced A1R expression. In binding studies, inosine bound to A1Rs with an affinity similar to adenosine. DCF had no effect on inosine actions. FDS augmented the antinociceptive effect of a low systemic dose of inosine and, at a higher dose, induced antinociception by itself. Collectively, these data indicate that inosine is an agonist for A1Rs with antinociceptive properties and a potency similar to adenosine and can be considered another endogenous ligand for this receptor.


Asunto(s)
Adenosina/análogos & derivados , Analgésicos/farmacología , Inosina/farmacología , Receptor de Adenosina A1/genética , Receptor de Adenosina A1/metabolismo , Adenosina Desaminasa/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dimensión del Dolor/métodos
15.
ABCS health sci ; 39(2): 96-100, maio-ago. 2014. tab
Artículo en Portugués | LILACS | ID: lil-746821

RESUMEN

A fibrose cística (FC), denominada também de mucoviscidose, é uma doença genética do tipo autossômica recessiva que acomete principalmente crianças e indivíduos de raça branca. O objetivo deste estudo foi propiciar uma visão sobre a FC, assim como as possíveis formas de tratamento fisioterapêutico. A pesquisa da literatura foi realizada nas bases de dados SciELO e PubMed, no período de abril de 2002 a março de 2013, através da seleção de artigos científicos referentes à FC, utilizando como palavras-chave: "fibrose cística", "fisioterapia em fibrose cística" e "fisioterapia respiratória". Por meio desta revisão, pôde-se observar que, apesar da complexidade da doença, a prática fisioterapêutica, com o uso das técnicas: tapotagem, vibração, drenagem postural (DP), huffing, oscilação oral de alta frequência (OOAF), drenagem autógena (DA) e o ciclo ativo da respiração (CAR), apresenta eficácia tanto no tratamento como na manutenção da qualidade de vida dos pacientes com FC.


Cystic fibrosis (CF), also denominated mucoviscidosis, is a genetic disease of autosomal recessive type that affects mainly children and Caucasians. The aim of this study was to provide an updated view on CF, as well as potential physiotherapy treatment. PubMed and SciELO databases have been searched, during April 2002 to March 2013, using the following keywords:"cystic fibrosis", "cystic fibrosis physiotherapy" and "respiratory physiotherapy". This review showed the complexity of the disease and the physiotherapy modalities such as tapping, vibration, postural drainage (PD), huffing, oral high frequency oscillation (OHFO), autogenic drainage (AD) and the active cycle technique (ACT) have effectiveness both in the treatment and in maintaining the quality of life of CF patients.


Asunto(s)
Fibrosis Quística , Modalidades de Fisioterapia , Moco
16.
J Alzheimers Dis ; 41(1): 43-60, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24577472

RESUMEN

Familial hypercholesterolemia is caused by inherited genetic abnormalities that directly or indirectly affect the function of the low-density lipoprotein (LDL) receptor. This condition is characterized by defective catabolism of LDL which results in increased plasma cholesterol concentrations and premature coronary artery disease. Nevertheless, there is increasing preclinical and clinical evidence indicating that familial hypercholesterolemia subjects show a particularly high incidence of mild cognitive impairment. Moreover, the LDL receptor (LDLr) has been implicated as the main central nervous system apolipoprotein E receptor that regulates amyloid deposition in distinct mouse models of ß-amyloidosis. In this regard, herein we hypothesized that the lack of LDLr would enhance the susceptibility to amyloid-ß-(Aß)-induced neurotoxicity in mice. Using the acute intracerebroventricular injection of aggregated Aß(1-40) peptide (400 pmol/mouse), a useful approach for the investigation of molecular mechanisms involved in Aß toxicity, we observed oxidative stress, neuroinflammation, and neuronal membrane damage within the hippocampus of C57BL/6 wild-type mice, which were associated with spatial reference memory and working memory impairments. In addition, our data show that LDLr knockout (LDLr(-/-)) mice, regardless of Aß treatment, displayed memory deficits and increased blood-brain barrier permeability. Nonetheless, LDLr(-/-) mice treated with Aß(1-40) peptide presented increased acetylcholinesterase activity, astrogliosis, oxidative imbalance, and cell permeability within the hippocampus in comparison with Aß(1-40)-treated C57BL/6 wild-type mice. Overall, the present study shows that the lack of LDLr increases the susceptibility to Aß-induced neurotoxicity in mice providing new evidence about the crosslink between familial hypercholesterolemia and cognitive impairment.


Asunto(s)
Amiloidosis/fisiopatología , Hipocampo/fisiopatología , Trastornos de la Memoria/fisiopatología , Corteza Prefrontal/fisiopatología , Receptores de LDL/metabolismo , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides , Amiloidosis/complicaciones , Amiloidosis/patología , Animales , Antioxidantes/metabolismo , Astrocitos/patología , Astrocitos/fisiología , Barrera Hematoencefálica/fisiopatología , Permeabilidad Capilar/fisiología , Permeabilidad de la Membrana Celular/fisiología , Modelos Animales de Enfermedad , Gliosis/patología , Gliosis/fisiopatología , Hipocampo/patología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Memoria a Corto Plazo/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroinmunomodulación/fisiología , Estrés Oxidativo/fisiología , Fragmentos de Péptidos , Corteza Prefrontal/patología , Receptores de LDL/genética , Memoria Espacial/fisiología , Superóxido Dismutasa/metabolismo
17.
Mol Nutr Food Res ; 57(11): 1938-49, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23861337

RESUMEN

SCOPE: We investigated the protective effect of the flavonoid myricitrin in dextran sulfate sodium (DSS) induced colitis as promising candidate for the treatment of ulcerative colitis which is considered an important worldwide public health problem. METHODS AND RESULTS: Male CD1 mice were provided with a solution of filtered water containing 3% w/v DSS ad libitum over a 5-day period followed by 2 days with normal drinking water. Myricitrin was administered orally, once a day, at the doses 1, 3, and 10 mg/kg of body weight. At the end of day 7th, the animals were euthanized and the colonic tissue was collected to be analyzed by RT-PCR, immunohistochemistry and Western blot. Our results showed that oral treatment with myricitrin exerts consistent anti-inflammatory action in DSS-induced acute colitis in mice by the inhibition of the Akt/phosphatidylinositol-3 kinase-dependent phosphorylation. Consequently, the phosphorylation of mitogen-activated protein kinases (MAPK) p38, extracellular signal-regulated protein kinase (ERK1/2), and c-Jun N-terminal kinase and of the nuclear factor B (NF-κB) was reduced and prevented an increase in the cytokines/chemokines levels. CONCLUSION: Together, these data reveal that the anti-inflammatory effect of myricitrin in DSS-induced colitis in mice is likely associated with its ability to prevent the activation of upstream kinases, such as phosphatidylinositol-3 kinase-dependent Akt, NF-κB, and mitogen-activated protein kinase.


Asunto(s)
Antiinflamatorios/administración & dosificación , Colitis/tratamiento farmacológico , Sulfato de Dextran/efectos adversos , Flavonoides/administración & dosificación , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Colitis/inducido químicamente , Colon/efectos de los fármacos , Colon/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteína Quinasa C-epsilon/genética , Proteína Quinasa C-epsilon/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
18.
Biochem Pharmacol ; 84(11): 1459-69, 2012 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-23000912

RESUMEN

Inflammatory bowel disease (IBD) affects millions of people worldwide but its pathophysiology remains unclear. Therefore, experimental models of colitis have contributed crucially for the understanding of IBD, and also in the investigations for effective therapies. Herein we investigated the kinetics of inflammatory mediator production and cell infiltration during acute and chronic dextran sodium sulfate (DSS)-induced colitis. The induction phases with DSS were characterized by severe disease activity with massive colonic polymorphonuclear infiltration and increased levels of tumor necrosis factor-α (TNF-α), keratinocyte-derived chemokine (CXCL1/KC), interleukin (IL)-17 and vascular adhesion molecule-1 (VCAM-1). Interestingly, in the recovery periods, we found marked increase of anti-inflammatory mediators IL-10, IL-4, transforming growth factor-ß (TGF-ß) and cyclooxygenase 2 (COX-2) that seems be essential for the resolution of intestinal inflammation. Furthermore, nuclear factor κB (NFκB) and regulatory T cell marker forkhead box P3 (FoxP3) were increased gradually during experimental colitis, demonstrating a discrepant profile response and evident immune disbalance in the chronic phase of intestinal mucosal inflammation. Taken together, these results provide valuable information for studies on DSS-induced colitis and especially for the identification of biomarkers that predict disease course and possible therapeutic interventions.


Asunto(s)
Sulfato de Dextran/administración & dosificación , Gastroenteritis/prevención & control , Animales , Western Blotting , Gastroenteritis/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena en Tiempo Real de la Polimerasa
19.
Neuropharmacology ; 63(4): 593-605, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22613837

RESUMEN

Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitating diseases, which still remain without a safe and adequate treatment. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. Here, we assessed the effects and the underlying mechanisms of action of euphol in preventing inflammatory and neuropathic pain. Oral treatment with euphol (30 and 100 mg/kg) reduced carrageenan-induced mechanical hyperalgesia. Likewise, euphol given through the spinal and intracerebroventricular routes prevented mechanical hyperalgesia induced by carrageenan. Euphol consistently blocked the mechanical hyperalgesia induced by complete Freund's adjuvant, keratinocyte-derived chemokine, interleukin-1ß, interleukin-6 and tumor necrosis factor-alpha associated with the suppression of myeloperoxidase activity in the mouse paw. Oral treatment with euphol was also effective in preventing the mechanical nociceptive response induced by ligation of the sciatic nerve and also significantly reduced the levels and mRNA of cytokines/chemokines in both paw and spinal cord tissues following i.pl. injection of complete Freund's adjuvant. In addition, the pre-treatment with either CB1R or CB2R antagonists, as well as the knockdown gene of the CB1R and CB2R, significantly reversed the antinociceptive effect of euphol. Interestingly, even in higher doses, euphol did not cause any relevant action in the central nervous system. Considering that few drugs are currently available for the treatment of chronic pain states, the present results provided evidence that euphol constitutes a promising molecule for the management of inflammatory and neuropathic pain states.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Edema/prevención & control , Hiperalgesia/prevención & control , Lanosterol/análogos & derivados , Neuralgia/prevención & control , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Conducta Animal/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Edema/inmunología , Edema/metabolismo , Técnicas de Silenciamiento del Gen , Miembro Posterior/efectos de los fármacos , Miembro Posterior/metabolismo , Hiperalgesia/inmunología , Hiperalgesia/metabolismo , Lanosterol/administración & dosificación , Lanosterol/antagonistas & inhibidores , Lanosterol/farmacología , Lanosterol/uso terapéutico , Masculino , Ratones , Neuralgia/inmunología , Neuralgia/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Dimensión del Dolor , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/genética , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo
20.
Biochem Pharmacol ; 83(4): 531-42, 2012 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-22155310

RESUMEN

Multiple sclerosis (MS) is a severe chronic T cell-mediated autoimmune inflammatory disease of the central nervous system (CNS), the existing therapy of which is only partially effective and is associated with undesirable side effects. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. However there are no reports about the effects and mechanisms of euphol in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here we report the effects and the underlying mechanisms of action of euphol in EAE. Euphol (1-10mg/kg) was administered orally at different time-points of EAE. Immunological and inflammatory responses were evaluated by real-time PCR, Western blot and flow cytometry assays. We provide evidence that euphol significantly attenuates neurological signs of EAE. These beneficial effects of euphol seem to be associated with the down-regulation of mRNA and protein expression of some pro-inflammatory mediators such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the CNS. Furthermore, in vitro, euphol consistently inhibited the T cell-mediated immune response including the production of T(H)1 and T(H)17 cytokines in spleen cells of untreated EAE animals. Likewise, oral euphol treatment inhibited the infiltration of T(H)17 myelin-specific cells into the CNS through the adhesion molecule, lymphocyte function-associated antigen 1 (LFA-1). Our findings reveal that oral administration of euphol consistently reduces and limits the severity and development of EAE. Therefore, euphol might represent a potential molecule of interest for the treatment of MS and other T(H)17 cell-mediated inflammatory diseases.


Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/prevención & control , Lanosterol/análogos & derivados , Animales , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Esquema de Medicación , Ingestión de Alimentos/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Lanosterol/química , Lanosterol/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
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