Neonatal morphine exposure and maternal deprivation alter nociceptive response and central biomarkers’ levels throughout the life of rats

In the present study, we investigated the effect of repeated neonatal morphine exposure and/or maternal deprivation(MD) on the nociceptive response and central biomarkers’ BDNF, IL-1β, and IL-4 levels at postnatal days 16(PND16), 30(PND30), and 60(PND60). At birth, the litters were standardized to contain 8 pups/dam (n = 58). From PND1 to PND10, the pups of the deprived groups were separated daily from their mothers for 3 h and divided into 5 groups: control(C), saline(S), morphine(M), deprived-saline(DS), and deprived-morphine (DM). The pups received subcutaneous injections of saline/morphine (5 μg) in the mid-scapular area between PND8 and PND14. Nociceptive responses were assessed by hot plate(HP) and tail-flick(TFL) tests and biomarker levels by ELISA. Thermal hyperalgesia(HP) was found in all assessments for the M, DS, and DM groups, and a decrease in nociceptive threshold(TFL) was found in the DS group at PND16; M and DM groups at PND30; and M, DS, and DM groups at PND60. There were interactions between treatment/deprivation/timepoint in all central biomarkers’ levels. The current study indicates that neonatal exposure to morphine and MD, which occurs in the pediatric ICU, can alter the nociceptive and neuroinflammatory responses

Transcranial direct current stimulation combined with exercise modulates the inflammatory profile and hyperalgesic response in rats subjected to a neuropathic pain model : long-term effects

Background: Behavioral alterations, like mechanical and thermal hyperalgesia, and modulation of biomarkers in the peripheral and central nervous systems (CNS) are markers of chronic pain. Transcranial direct current stimulation (tDCS) with exercise is a promising therapy for pain due to its neuromodulatory capacity. Objective: To assess the individual effects of tDCS, exercise, and the two combined on the nociceptive response and BDNF, IL-1b, and IL-4 levels in the CNS structures of rats in a chronic pain model. Methods: For 8 consecutive days after the establishment of chronic neuropathic pain by inducing a constriction injury to the sciatic nerve (CCI), the rats received tDCS, exercise, or both treatments combined (20 min/day). The hyperalgesic response was assessed by von Frey and hot plate tests at baseline, 7, and 14 days after CCI surgery and immediately, 24 h, and 7 days after the end of treatment. The BDNF, IL1b, and IL-4 levels were assessed in the cerebral cortex, brainstem, and spinal cord by enzyme-linked immunosorbent assay at 48 h and 7 days after the end of treatment. Results: The CCI model triggered marked mechanical and thermal hyperalgesia. However, bimodal tDCS, aerobic exercise, and the two combined relieved nociceptive behavior for up to 7 days following treatment completion. Conclusions: Bimodal tDCS, aerobic exercise, or both treatments combined promoted analgesic effects for neuropathic pain. Such effects were reflected by cytokine modulation throughout the spinal cordbrainstem-cerebral cortex axis

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Avaliação pré-clínica da estimulação transcraniana por corrente contínua : uma nova abordagem terapêutica para o tratamento da epilepsia

Epilepsia é o termo utilizado para descrever uma síndrome cerebral crônica de diversas etiologias caracterizada por recorrentes crises convulsivas devido a descargas neuronais excessivas, sendo um dos principais transtornos neurológicos em adultos e crianças. Apesar da grande variedade de fármacos antiepiléticos, muitos pacientes relatam efeitos adversos que impedem o seu uso continuado. Além disso, há um contingente de pacientes refratário aos tratamentos farmacológicos disponíveis. Portanto, o desenvolvimento de novas abordagens terapêuticas que possam fazer uso de mecanismos múltiplos de ação e efeitos adversos minimizados – como a estimulação transcraniana por corrente contínua (ETCC) – é considerado de grande interesse na terapêutica. Poucos estudos pré-clínicos utilizando a técnica de ETCC foram traduzidos em pesquisa clínica (número de sessões e efeitos na frequência de crises). Além disto, a maioria dos achados não foi testada (efeitos de ETCC no estado de mal epilético, crises de ausência, efeitos neuroprotetores no hipocampo e seu uso combinado com um fármaco específico). Já os estudos clínicos com ETCC foram testados em várias síndromes epilépticas, mas grande parte destes estudos clínicos não foram previamente avaliada em estudos pré-clínicos (encefalite de Rasmussen, epilepsia resistente a medicamentos e epilepsia por esclerose hipocampal). É importante salientar que, a maioria dos estudos envolvendo epilepsia e ETCC mostra resultados positivos. Nesta tese foi avaliado o efeito da ETCC em ratos submetidos ao modelo de kindling por pentilenotetrazol (PTZ), sobre parâmetros comportamentais convulsivos e bioquímicos, bem como comparou o efeito da estimulação anodal e catodal associadas ou não ao fármaco anticonvulsivante diazepam, buscando avaliar um possível sinergismo entre ETCC e o tratamento farmacológico. Os parâmetros neuroquímicos avaliados foram níveis de IL1-, TNFα, NGF e BDNF) em hipocampo e córtex, após o tratamento de kindling e após a ETCC. Nem a a estimulação transcraniana por corrente contínua anodal (ETCC-a) nem a a estimulação transcraniana por corrente contínua catodal (ETCC-c) reduziram a ocorrência de convulsões clônicas do membro anterior. Porém quando associado ao diazepam (DZP), a ETCC-c (ETCC-c/DZP0.15) aumentou a latência para a primeira convulsão no quarto e sexto dias. Os níveis de IL-1β do hipocampo foram reduzidos por ETCC-c e ETCC-c/DZP0.15. Por outro lado, esses tratamentos induziram um aumento nos níveis corticais de IL-1β. Os níveis de TNF-α no hipocampo não foram alterados por ETCC-c ou ETCC-a, mas ETCC-c e ETCCc/ DZP0.15 aumentaram seus níveis no córtex cerebral. Os níveis de NGF cortical foram aumentados pela ETCC-c e pela ETCC-c/DZP0.15. ETCC-a/DZP0.15 reduziu os níveis de BDNF no hipocampo e ETCC-c/DZP0.15 aumentou esses níveis no córtex cerebral. Em conclusão, a ETCC-c isolada ou em combinação com uma dose baixa de DZP mostrou efeitos neuroprotetores, melhorando os níveis de neurotrofinas centrais e diminuindo os níveis de IL-1β hipocampal após o estímulo repetido induzido por PTZ, sem efeito estatisticamente significativo no comportamento convulsivo. Esta técnica pode ter uso potencial na epilepsia muito provavelmente como adjuvante na farmacoterapia convencional.Epilepsy is the term used to describe a chronic cerebral syndrome of various etiologies characterized by recurrent seizures due to excessive neuronal discharges being one of the major neurological disorders in adults and children. Despite the wide variety of antiepileptic drugs, many patients report adverse effects that prevent their continued use. Besides, there is a contingent of patients refractory to available pharmacological treatments. Therefore, the development of new therapeutic approaches that may make use of multiple mechanisms of action and minimized adverse effects - such as transcranial direct current (tDCS) stimulation - is considered of great therapeutic interest. Few preclinical studies using the tDCS technique have been translated into clinical research (number of sessions, effects on the frequency of seizures). In addition, most of the findings were not tested (tDCS effects on the status of epilepsy, absence crises, neuroprotective effects on the hippocampus and their combined use with a specific drug). Clinical studies with tDCS have been tested in several epilepsy syndromes, but most of these clinical studies have not been previously evaluated in preclinical studies (Rasmussen encephalitis, drug resistant epilepsy and epilepsy due to hippocampal sclerosis). It is important to note that most studies involving epilepsy and tDCS show positive results. In this thesis, the effect of tDCS on rats submitted to the kindling model by pentylenetetrazole (PTZ) on behavioral and biochemical parameters was evaluated, as well as the effect of anodal and catodal stimulation associated or not with the anticonvulsant drug diazepam, in order to evaluate a possible synergism between the tDCS and the pharmacological treatment. The neurochemical parameters evaluated were levels of IL1-β, TNFα, NGF and BDNF) in hippocampus and cortex, after the kindling treatment and tDCS. Neither anodal-tDCS (a-tDCS) nor cathodaltDCS (c-tDCS) reduced the occurrence of clonic seizures of the anterior limb. Associated with diazepam (DZP), c-tDCS (c-tDCS/DZP0.15) increased the latency for the first seizure on the 4th and 6th days. The levels of IL-1β from the hippocampus were reduced by c-tDCS and c-tDCS/DZP0.15. On the other hand, these treatments induced an increase in the cortical levels of IL-1β. TNF-α levels in the hippocampus were not altered by c-tDCS or a-tDCS, but c-tDCS and c-tDCS/DZP0.15 increased their levels in the cerebral cortex. Cortical NGF levels were increased by c-tDCS and ctDCS/ DZP0.15. a-tDCS/DZP0.15 reduced levels of BDNF in the hippocampus and ctDCS/ DZP0.15 increased those levels in the cerebral cortex. In conclusion, c-tDCS alone or in combination with a low dose of DZP showed neuroprotective effects, improving central neurotrophin levels and decreasing levels of hippocampal IL-1β after repeated PTZ-induced stimulation, with no statistically significant effect on convulsive behavior. This technique may have potential use in epilepsy most likely as adjuvant in conventional pharmacotherapy