51 research outputs found

    CURRENT UNDERSTANDING OF HYPERPOLARIZATION-ACTIVATED AND CYCLIC NUCLEOTIDE-GATED (HCN) CHANNELS: A REVIEW

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    Hyperpolarization-activated and Cyclic Nucleotide-gated (HCN) channels with significant physiological role are found to be present in heart and brain. These channels have got four subtypes encoded by four different genes. They play significant role in maintainance of cardiac rhythm and neuronal excitability with definite but partially defined role in development of arrhythmia, epilepsy and neuropathic pain.  These are also known as pace maker channels. In present review we will mainly discuss electrophysiology of neurons and SA node in special reference to HCN channel. In the heart mainly HCN4 subtype is present while in brain all four isotype have been found where they are involved in numerous neuronal functions i.e. dendrite c integration, memory, thalamo-cortical rhythm etc. Further in review we will also discuss in brief the physiology and uniqueness of this ion channel and disorders especially epilepsy, neuropathic pain and cardiac arrhythmia, due to the malfunctioning of these ion channels. The newer possibilities of modifying this ion channel along with the drugs acting will also be discussed. Keywords: HCN ion channels, Arrythmia, Epilepsy, Neuropathic Pain

    Neuronal differentiation of GFP expressing P19 embryonal carcinoma cells by deprenyl, an antiparkinson drug

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    زمینه و هدف: سلول های P19 دودمانی از سلول های کار سینومای جنینی چند استعدادی هستند که قادرند در محیط کشت حاوی سرم رشد نموده و برای تمایز به هر سه دودمان مزودرمی، آندودرمی و اکتودرمی القا شوند. با استفاده از روش های استاندارد ترانسفکشن می توان توالی DNA خارجی را به این سلول ها وارد کرده و عملکرد و تمایز سلولی را بررسی کرد. این تحقیق با هدف القای فنوتیپ عصبی در سلول های P19 ترانسفکت شده با ژن پروتئین فلوئورسانت سبز (GFP) با استفاده از داروی ضد پارکینسونی دپرنیل صورت گرفت. روش بررسی: در این مطالعه توصیفی آزمایشگاهی از روش رسوب کلسیم فسفات جهت وارد کردن پلاسمید pML8 حاوی ژن GFP و ژن مقاوم به پیورومایسین به این سلول ها استفاده شد. سلول ها با استفاده از محیط کشت MEM-A (Minimum Essential Medium Alpha) حاوی 15 درصد سرم گاوی جنینی کشت داده شدند. در اینجا غلظت 8-10 مولار دپرنیل برای القای تمایز اجسام شبه جنینی به دودمان عصبی استفاده شد. جهت ارزیابی تمایز سلول های P19 بررسی موفولوژی با استفاده از رنگ آمیزی اختصاصی کرزیل ویوله انجام شد. به علاوه برای ردیابی پروتئین های ویژه سلول های عصبی مانند سیناپتوفیزین و بتاتوبولین III از روش ایمنوفلورسنس استفاده شد. یافته ها: ضمن تولید سلول های P19 ترانسفکت شده پایدار، تمایز عصبی این سلول ها تحت تأثیر عامل القایی دپرنیل انجام شد. نورون های GFP مثبت مشتق شده از سلول های کار سینومای جنینی نشانگرهای ویژه سلول های عصبی را بیان کردند. نتیجه گیری: سلول های تمایز یافته GFP مثبت می توانند در مطالعات پیوندی و پژوهش های پایه ای مرتبط با سلول درمانی و بیماری های تحلیل سیستم عصبی مورد استفاده قرار گیرند

    Risk factors for chronic postsurgical pain in visceral surgery: a matched case-control analysis.

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    PURPOSE Chronic postsurgical pain (CPSP) after abdominal visceral surgery is an underestimated long-term complication with relevant impact on health-related quality of life and socioeconomic costs. Early identification of affected patients is important. We aim to identify the incidence and risk factors for CPSP in this patient population. METHODS Retrospective case-control matched analysis including all patients diagnosed with CPSP after visceral surgery in our institution between 2016 and 2019. One-to-two case-control matching was based on operation category (HPB, upper-GI, colorectal, transplantation, bariatric, hernia and others) and date of surgery. Potential risk factors for CPSP were identified using conditional multivariate logistic regression. RESULTS Among a cohort of 3730 patients, 176 (4.7%) were diagnosed with CPSP during the study period and matched to a sample of 352 control patients. Independent risk factors for CPSP were age under 55 years (OR 2.64, CI 1.51-4.61), preexisting chronic pain of any origin (OR 3.42, CI 1.75-6.67), previous abdominal surgery (OR 1.99, CI 1.11-3.57), acute postoperative pain (OR 1.29, CI 1.16-1.44), postoperative use of non-steroidal anti-inflammatory drugs (OR 3.73, OR 1.61-8.65), opioid use on discharge (OR 3.78, CI 2.10-6.80) and length of stay over 3 days (OR 2.60, CI 1.22-5.53). Preoperative Pregabalin intake was protective (OR 0.02, CI 0.002-0.21). CONCLUSION The incidence of CPSP is high and associated with specific risk factors, some of them modifiable. Special attention should be given to sufficient treatment of preexisting chronic pain and acute postoperative pain

    Análise dos mecanismos neurofisiológicos envolvidos no efeito da terapia manual (mobilização articular) na dor aguda e crônica

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    Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Florianópolis, 2013Evidências sugerem que as técnicas de terapia manual são efetivas no tratamento de problemas músculo-esqueléticos incluindo dor lombar, síndrome do túnel do carpo, osteoartrite de joelho e quadril. No entanto, apesar dos seus resultados positivos e da sua eficácia, os mecanismos neurofisiológicos destas técnicas foram pouco estudados. Assim, o objetivo deste estudo foi de verificar o efeito da mobilização articular do tornozelo (MAT) na dor aguda e crônica de origem pós-operatória e neuropática, respectivamente, além de investigar os mecanismos de ação envolvidos neste efeito. Para tal, foram utilizados camundongos Swiss machos (25-35g) submetidos ao modelo de dor pós-operatória através da incisão plantar (IP) e ao tratamento com a MAT por 3 ou 9 minutos. A avaliação da dor (nocicepção) foi realizada através da mensuração da hiperalgesia mecânica, utilizando-se o filamento de von Frey (0,4 g) pelo método de freqüência de resposta, antes e após a incisão e 30 minutos após a MAT, diariamente. Além disto, os animais também receberam tratamento diário com MAT durante 9 minutos por 6 dias. No estudo do mecanismo de ação, as análises foram realizadas 24 horas após a IP e o envolvimento dos sistemas opioidérgico, adenosinérgico, monoaminérgico e endocanabinoidérgico no efeito da MAT foram investigados. Para avaliar a influência da MAT sobre a dor neuropática, utilizou-se o modelo do esmagamento do nervo isquiático em ratos Wistar machos (250-280 g), sendo que os animais receberam 15 tratamentos (9 minutos de MAT) em dias alternados. A hiperalgesia mecânica foi avaliada antes e ao longo do tratamento por 5 semanas. Trinta e cinco dias após a lesão, a medula espinal (L4-L5) foi coletada para determinação da imunoreatividade de CD11b/c (microglia) e de GFAP (astrócito). Os resultados demonstram que 9 minutos de MAT reduz a hiperalgesia mecânica induzida pela IP, efeito mediado pelos sistemas opioidérgico, adenosinérgico, monoaminérgico e endocanabinoidérgico. Além disso, a MAT produz efeito antihiperalgésico e neuroregenerativo na lesão do nervo isquiático, ocorrendo estes efeitos em paralelo com a redução da imunoreatividade para microglia e astrócito na medula espinal. Assim, conclui-se que: i) a MAT apresenta grande potencial terapêutico na redução da dor pós-operatória e neuropática, bem como em acelerar a regeneração nervosa periférica; ii) os sistemas opioidérgico, adenosinérgico, monoaminérgico e endocanabinoidérgico estão envolvidos no efeito antihiperalgésico da MAT e; iii) a redução da ativação de células microgliais e astrocitárias na medula espinal contribui para o efeito antihiperalgésico da MAT. Neste sentido, estes dados fornecem à literatura substanciais subsídios neurofisiológicos do efeito terapêutico da MAT para o direcionamento de futuros ensaios clínicos.Abstract : Manual therapy techniques are effective in the treatment of musculoskeletal problems including low back pain, carpal tunnel syndrome, osteoarthritis of the knee and hip. However, despite their positive results and its effectiveness, the neurophysiological mechanisms of these techniques are not thoroughly known. This study investigates the effect of ankle joint mobilization (AJM) in acute and chronic pain of postoperative and neuropathic origin, respectively, and the possible mechanisms involved in this effect. To this end, male Swiss mice (25-35g) were subjected to a plantar incision procedure (PI), a model of postoperative pain, and treated with AJM for 3 or 9 minutes. Pain levels (nociception) were assessed by measuring mechanical hyperalgesia to a von Frey filament (0.4g) by the method of frequency response before and after PI and 30 minutes after daily AJM. In addition, the animals also received daily 9 minutes sessions with AJM for 6 days. For the investigation of the mechanisms of action, the tests were performed 24 hours after PI and opioid, adenosinergic, monoaminergic and endocannabinoid systems were analyzed at different sites (central, peripheral and local). In order to evaluate the influence of AJM on neuropathic pain the model of sciatic nerve crush was used in male Wistar rats (250-280 g). These animals received 15 treatments (9 minutes AJM) on alternate days. The mechanical hyperalgesia was assessed before and during treatment for 5 weeks. Thirty-five days after injury, the spinal cord (L4-L5) was collected for determination of immunoreactivity to CD11b / c (microglia) and GFAP (astrocytes). The results show that 9 minutes AJM reduces the mechanical hyperalgesia induced by PI, an effect that is mediated by opioid, adenosinergic, monoaminergic and endocannabinoid systems. Finally, we showed that AJM produces antihyperalgesic and regenerative effects, and these effects occur in parallel to the reduction in immunoreactivity to GFAP CD11b/c in the spinal cord. In conclusion, we demonstrated that: i) AJM has great therapeutic potential in reducing postoperative and neuropathic pain as well as accelerates peripheral nerve regeneration; ii) opioid, adenosinergic, monoaminergic and endocannabinoid systems are involved in the antihyperalgesic effect of AJM and iii) reducing the activation of microglial cells and astrocytes in the spinal cord contributes to the antihyperalgesic effect of AJM. Thus, these data provide substantial input to the neurophysiological literature of the therapeutic effect of AJM that will help to guide future clinical trials

    Ilex paraguariensis extract as drugs alternative for pain

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    Pain is a common and distressing symptom of many diseases and its clinical treatment generally involves analgesics and anti-inflammatory drugs. This study evaluated the toxicity of Ilex paraguariensis A. St.-Hil. (Aquifoliaceae) aqueous extract (leaves, petioles and branches) and its performance in nociceptive response. Hepatotoxicity, psychostimulant test and evaluation of enzyme markers for liver damage were also tested. Chromatographic analysis by UPLC-MS demonstrated a series of isomeric monocaffeoylquinic acids, isomers of dicaffeoylquinic acids, flavonol glycosides, and saponins. Phase I and II of nociception were obtained for meloxicam, dexamethasone and aqueous Ilex paraguariensis extract. Ilex paraguariensis extract concentration was negatively correlated (R = –0.887) with alanine aminotransferase (p < 0.05) in acetaminophen-induced hepatotoxicity test, indicating an hepatoprotective activity of this extract. Ilex paraguariensis extract also presented analgesic properties equivalent to drugs that already have proven efficacy. Notably, administration of multiple doses of Ilex paraguariensis extract was considered safe from the therapeutic point of view

    The anti-inflammatory effect of Ilex paraguariensis A. St. Hil (Mate) in a murine model of pleurisy.

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    Ilex paraguariensis is a native plant from Southern America, where it is used as a beverage. In traditional medicine, it is used to treat many diseases including inflammation. However, we do not yet know precisely how this effect occurs. We therefore evaluated its anti-inflammatory effect in a murine model of pleurisy. The standardized CE, BF and ARF fractions, Caf, Rut and CGA were able to reduce leukocyte migration, exudate concentration, MPO and ADA activities and NOx levels. Moreover, I. paraguariensis also inhibited the release of Th1/Th17 pro-inflammatory cytokines, while increasing IL-10 production and improving the histological architecture of inflamed lungs. In addition, its major compounds decreased p65 NF-κB phosphorylation. Based on our results, we can conclude that I. paraguariensis exerts its anti-inflammatory action by attenuating the Th1/Th17 polarization in this model. This fact suggests that the use of this plant as a beverage can protect against Th1/Th17 inflammatory diseases

    Evidence for a Role of Endocannabinoids, Astrocytes and p38 Phosphorylation in the Resolution of Postoperative Pain

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    An alarming portion of patients develop persistent or chronic pain following surgical procedures, but the mechanisms underlying the transition from acute to chronic pain states are not fully understood. In general, endocannabinoids (ECBs) inhibit nociceptive processing by stimulating cannabinoid receptors type 1 (CB(1)) and type 2 (CB(2)). We have previously shown that intrathecal administration of a CB(2) receptor agonist reverses both surgical incision-induced behavioral hypersensitivity and associated over-expression of spinal glial markers. We therefore hypothesized that endocannabinoid signaling promotes the resolution of acute postoperative pain by modulating pro-inflammatory signaling in spinal cord glial cells.To test this hypothesis, rats receiving paw incision surgery were used as a model of acute postoperative pain that spontaneously resolves. We first characterized the concentration of ECBs and localization of CB(1) and CB(2) receptors in the spinal cord following paw incision. We then administered concomitant CB(1) and CB(2) receptor antagonists/inverse agonists (AM281 and AM630, 1 mg x kg(-1) each, i.p.) during the acute phase of paw incision-induced mechanical allodynia and evaluated the expression of glial cell markers and phosphorylated p38 (a MAPK associated with inflammation) in the lumbar dorsal horn. Dual blockade of CB(1) and CB(2) receptor signaling prevented the resolution of postoperative allodynia and resulted in persistent over-expression of spinal Glial Fibrillary Acidic Protein (GFAP, an astrocytic marker) and phospho-p38 in astrocytes. We provide evidence for the functional significance of these astrocytic changes by demonstrating that intrathecal administration of propentofylline (50 microg, i.t.) attenuated both persistent behavioral hypersensitivity and over-expression of GFAP and phospho-p38 in antagonist-treated animals.Our results demonstrate that endocannabinoid signaling via CB(1) and CB(2) receptors is necessary for the resolution of paw incision-induced behavioral hypersensitivity and for the limitation of pro-inflammatory signaling in astrocytes following surgical insult. Our findings suggest that therapeutic strategies designed to enhance endocannabinoid signaling may prevent patients from developing persistent or chronic pain states following surgery
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