ß-caryophyllene, a cannabinoid receptor 2 agonist, decreases the motivational salience and conditioning place preference for palatable food in female mice.

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.

Immunohistochemistry of resorption and inflammation factors in the periodontal ligament of human deciduous teeth.

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.

Effect of photobiomodulation therapy (660 nm and 830 nm) on carrageenan-induced edema and pain behavior in mice / Efeito da terapia por fotobiomodulação (660 nm e 830 nm) no comportamento da dor e edema induzidos por carragenina em camundongos

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.

Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.

Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.

Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512-2 Toxin in Persistent Pain Models.

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.

Modified montmorillonite-bacterial cellulose composites as a novel dressing system for pressure injury.

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.

Pramipexole, a dopamine D3/D2 receptor-preferring agonist, attenuates reserpine-induced fibromyalgia-like model in mice.

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.

Immunohistochemistry of resorption and inflammation factors in the periodontal ligament of human deciduous teeth

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.

Antidepressant-like effect of rosmarinic acid during LPS-induced neuroinflammatory model: The potential role of cannabinoid receptors/PPAR-γ signaling pathway.

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.

Cell culture of the normal human mammary gland cultivated in monolayer - A mini systematic review.

The mammary glands are constituted of different cell types. For example, the epithelial cells appear as the target in many studies since they produce and secrete milk during lactation and are the origin of many human breast cancers. Mammary gland biology is characterized by dynamic tissue growth, function and regression phases, which are understood mainly due to tissue culture studies. Cell culture is probably one of the most used in vitro scientific models, and the most common research model is still the two-dimensional (2D) culture system. Different approaches and conditions have been tested and used to improve the isolation, growth, yield and maintenance of viability of mammary gland cells. Therefore, our study aimed to explore and summarize the cell culture techniques with normal human mammary gland cells cultured in a monolayer. A search strategy was conducted using the electronic databases 'PubMed', 'Scopus' and 'Virtual Health Library'. The search was carried out using the keywords 'cell culture' and 'mammary gland' and 'human'. The main search was carried out by two authors between July and August 2021. In addition, we performed a review matrix elaborated in a spreadsheet to organize and systematize information about each article for inclusion. A total of 11 studies were included in the review and have conducted qualitative analyses on them. Although studies of these cells have been reported since the 1970 s, most found are from the last decade and are largely carried out in the USA. In addition, it was possible to verify the Human Mammary Epithelial Cells (HMEC) primary culture obtained from breast surgery as the main cell type studied. These cells are cultivated in Dulbecco's Modified Eagle Medium (DMEM) and M87A medium with diverse supplements. Finally, there was a diversity in the use of dissociation reagents and a lack of information about cryopreservation. We have observed detailed methodological information about these study models, which would propose further investigations.

Exercise Reduces Pain and Deleterious Histological Effects in Fibromyalgia-like Model.

Fibromyalgia (FM) is characterized by chronic pain and associated comorbidities such as fatigue, anxiety, depression, and sleep disorders. There is a large amount of evidence regarding the benefits of physical exercise in controlling chronic pain. However, there is no consensus on which exercise modality is most suitable and the real benefits of this intervention to treat FM symptoms. The present study investigated the analgesic and antidepressant effects and morphophysiological responses induced by different physical exercise (aerobic and strength protocols) during the experimental model of FM. Spontaneous pain, mechanical hyperalgesia, thermal allodynia, depression-related behavior, and locomotor activity were evaluated weekly, as well as the morphological evaluation of the spinal cord and dorsal root ganglion. Aerobic and strength training protocols consistently abolished nociceptive behaviors, reducing spontaneous pain scores, cold allodynia, and frequency of response to mechanical hyperalgesia. The strength exercise modulated the depressive-like behavior. Finally, our data demonstrated that physical exercise performed for two weeks increased the number of glial cells in the dorsal root horn. However, it was not sufficient to control the other deleterious effects of the reserpine model on the spinal cord and the dorsal root. Together, these results demonstrated that different physical exercise modalities, when performed regularly in mice, proved to be effective and safe non-pharmacological alternatives for the treatment of FM. However, some gaps have yet to be studied regarding the neuroadaptive effects of physical exercise.

In silico, in vitro and in vivo studies indicate resveratrol analogue as a potential alternative for neuroinflammatory disorders.

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.

(-)-ß-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis.

(-)-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.

Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor.

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.

Kinin receptors: Key regulators of autoimmunity.

The central function of the immune system is to protect the host from environmental agents such as microbes or chemicals, thereby preserving the integrity of the body, and preventing the onset of illness and infection. Moreover, the immune system is constantly challenged to discriminate self vs. non-self and mediate the correct response, a phenomenon called self-tolerance. The failure of mechanisms responsible for self-tolerance and induction of an immune response against components of the self, induces autoimmunity and culminates however, in several autoimmune diseases. The precise etiology of autoimmune diseases is not known, although the classic sign of an autoimmune disease is inflammation. In this context, kinins are a family of peptides involved in different physiological and pathological states, comprising inflammatory, vascular and pain processes, and are highly relevant as well as to a variety of diseases including hypertension, kidney diseases, Alzheimer's disease, cancer, obesity, epilepsy and traumatic injuries. These kinin effects are mediated by two related G-protein-coupled receptors named the bradykinin receptors (BKRs), B1 and B2. The kallikrein-kinin system (KKS) and their receptors appear to be involved in both the development and progression of autoimmune diseases, suggesting that modulators of BKRs, administered in monotherapy or in combination with existing therapies, may represent a potential new venue for an effective autoimmune disease treatment. This review article highlights historical and recent progress in understanding the role of BKRs as potential therapeutics for a number of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases, and others.

Antidepressant-like effect of pramipexole in an inflammatory model of depression.

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.

TRPV1 channel inhibition contributes to the antinociceptive effects of Croton macrostachyus extract in mice.

BACKGROUND: Previous study showed that extracts from Croton macrostachyus (Euphorbiaceae) exhibit analgesic effects in acute pain models. The present study evaluates the antinociceptive properties of the methanol/methylene chloride extract (MECM) of the stem bark of this plant using mice models of persistent inflammatory and neuropathic pain, and assesses its mechanism of action. METHODS: MECM was tested on Complete Freund adjuvant (CFA)-induced persistent thermal and mechanical pain, neuropathic pain induced by partial sciatic nerve ligation (PSNL), prostaglandin E2 (PGE2)-induced acute mechanical hyperalgesia, as well as on nociception induced by capsaicin in mice. Mechanical hyperalgesia was assessed using von Frey hair in awake mice. The mechanism of action of MECM was evaluated by using glibenclamide on PGE2-induced hyperalgesia or rimonabant on capsaicin-induced pain. RESULTS: MECM administered orally at the doses of 250 and 500 mg/kg, induced long lasting and significant antihyperalgesic effects on CFA-inflammatory and PSNL-induced neuropathic pain. MECM significantly reduced the mechanical hyperalgesia induced by PGE2 either when administered preventively or therapeutically. MECM also significantly and time dependently inhibited the capsaicin-induced nociception. These effects were not affected by glibenclamide or by rimonabant. CONCLUSIONS: The present results demonstrate that the oral administration of MECM to mice resulted in long lasting antihyperalgesic activity in inflammatory and neuropathic pain as well as in acute and persistent pain. The mechanism underlying the long lasting MECM antihyperalgesic effect is currently unknown, but might be mediated, at least partially, through the modulation of TRPV1 receptors.

Adenosine A1 receptor-dependent antinociception induced by inosine in mice: pharmacological, genetic and biochemical aspects.

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.

Prática fisioterapêutica no tratamento da fibrose cística / Physiotherapeutic modalities in the treatment of cystic fibrosis

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.