Efeito do exercício físico na resposta antinociceptiva induzida por estimulação transcraniana por corrente contínua (ETCC) em ratos submetidos a um modelo de dor neuropática

Introdução: Dor neuropática crônica origina-se por lesão ou doença no sistema nervoso somatossensorial, e é frequentemente acompanhada por comorbidades como ansiedade, depressão, déficits cognitivos, redução na qualidade de vida, dentre outros. Além do aspecto multidimensional, a refratariedade ao tratamento farmacológico faz com que o manejo desta doença se torne um desafio. Logo, a busca por terapêuticas complementares que contribuam no tratamento da dor crônica e suas comorbidades devem ser encorajados. Objetivos: Investigar os efeitos da associação entre a estimulação transcraniana por corrente contínua (ETCC) e exercício sobre parâmetros comportamentais e bioquímicos em ratos submetidos a um modelo de dor neuropática. Materiais e métodos: Ratos Wistar (~ 60 dias) foram inicialmente divididos em 3 grupos: controle; sham-dor e dor. A dor neuropática foi induzida pela constrição crônica do nervo isquiático esquerdo (CCI) sob anestesia com isoflurano. No 14º dia, os animais foram subdivididos em 13 grupos: controle; sham-dor; sham-dor+sham/ETCC; sham-dor+exercício; sham-dor+ETCC; sham-dor+sham/ETCC+exercício; sham-dor+ETCC+exercício; dor; dor+sham/ETCC; dor+exercício; dor+ETCC; dor+sham/ETCC+exercício; dor+ETCC+exercício. Hiperalgesia mecânica e térmica foram avaliadas pelos testes do von Frey e placa quente nos tempos: basal; 7º e 14º dias após a CCI, e imediatamente, 24h e 7 dias após os tratamentos. O comportamento do tipo ansioso foi avaliado por meio do labirinto em cruz elevado (elevated plus maze-EPM) 24h e 7 dias após a última sessão de tratamento. Do 15º ao 22º dia, os ratos receberam ETCC bimodal (0.5mA), exercício (70% VO2máx) ou a combinação de ambos uma vez ao dia por 20 minutos. Em 48h ou 7 dias após o final dos tratamentos, os ratos foram eutanasiados, e o córtex cerebral, hipocampo, tronco encefálico, medula espinhal e nervo isquiático foram coletados para dosagens de citocinas e fatores neurotróficos pela técnica de ELISA. Dados comportamentais foram analisados pela equação de estimativas generalizadas (GEE) ou ANOVA de 3 vias seguida de Bonferroni; e os resultados bioquímicos foram analisados por ANOVA de 3 ou 4 vias seguida de Bonferroni. Todos os procedimentos experimentais foram aprovados pela CEUA/HCPA: #20170061; #20180034. Resultados: Em nosso estudo observamos que a ETCC e/ou exercício físico reverteram completamente a hiperalgesia térmica em todos os períodos de tempo analisados, enquanto que a hiperalgesia mecânica foi parcialmente revertida e promoveu um efeito sinérgico em 7 dias após o término do tratamento. Em relação ao comportamento do tipo ansioso, foi observado que a ETCC combinado ao exercício aumentou o número de entradas nos braços abertos (EOA) e reduziu o tempo de permanência nos braços fechados (TCA). Do ponto de vista bioquímico, observamos que a associação entre ETCC e exercício, aumentou os níveis de BDNF (7 dias) e reduziu a IL-4 no córtex cerebral. No hipocampo, a combinação entre tratamentos desencadeou efeitos opostos ao longo do tempo, em 48h após o final dos tratamentos houve um aumento no conteúdo de BDNF, enquanto que no 7º dia, foi observado uma redução nos níveis desta neurotrofina e de TNF-α. Em relação ao tronco encefálico e medula espinhal (7 dias), a ETCC combinada ao exercício aumentou os níveis de IL-4, enquanto que no nervo isquiático houve um aumento no BDNF (48 h) e IL-10 (7 dias) promovidos pelas técnicas combinadas. Conclusão: Em resumo, nossos achados demonstram que a combinação de técnicas neuromoduladoras é eficaz em promover efeitos antinociceptivos e ansiolíticos por meio da modulação de parâmetros bioquímicos e moleculares em estruturas do sistema nervoso periférico e central. Portanto, estas terapêuticas não farmacológicas são promissoras adjuvantes no tratamento da dor crônica e suas comorbidades. Adicionalmente, é possível observar que estas técnicas promovem a modulação de parâmetros neuroquímicos de forma tecido, estado ou tempo-dependente.Background: Neuropathic pain arises from an injury or disease in the peripheral or central nervous system, being accompanied by comorbidities such as anxiety, depression, cognitive impairments, reduction of quality of life, among others. In addition to the multidimensional aspect, the refractoriness to the pharmacological treatment makes the management of this disease a challenge. Therefore, the search for complementary therapies that add to the chronic pain treatment and its comorbidities should be encouraged. Aim: To investigate the effects of transcranial direct current stimulation (tDCS) combined with exercise on behavioral and biochemical parameters in rats subjected to a neuropathic pain model. Material and methods: Male Wistar rats (~ 60 days) were divided into 3 groups: control; sham-pain e pain. Neuropathic pain was induced by chronic constriction injury of the left sciatic nerve (CCI) under isoflurane anesthesia. On 14º day, rats were subdivided into 13 groups: control; sham-pain; sham-pain+sham/tDCS; sham-pain+exercise; sham-pain+tDCS; sham-pain+sham/tDCS+exercise; sham-pain+tDCS+exercise; pain; pain+sham/tDCS; pain+exercise; pain+tDCS; pain+sham/tDCS+exercise; pain+tDCS+exercise. Mechanical and thermal hyperalgesia were assessed by von Frey e hot plate tests at: baseline; 7º e 14º days after CCI, and immediately, 24h e 7 days after the end of treatments. Anxiety-like behavior was assessed in the elevated plus maze (EPM) at 24h e 7 days after the last treatment session. From 15th up to 22nd day, rats received bimodal tDCS (0.5mA), exercise (70% VO2max) or the combination of both once a day for 20 minutes. At 48h or 7 days after the end of treatments, rats were killed, and the cerebral cortex, hippocampi, brainstem, spinal cord and sciatic nerve were harvested for cytokines and growth factors quantification by ELISA. Behavioral data were analyzed by generalized estimate equations (GEE) or 3-way ANOVA followed by Bonferroni; whilst biochemical data were analyzed by 3 or 4-way ANOVA/Bonferroni. All experimental procedures were approved by CEUA/HCPA #20170061; #20180034. Results: In our study, it was observed that tDCS and/or physical exercise fully reverted thermal hyperalgesia in all time point assessed, while mechanical hyperalgesia was partially reverted and promoted a synergistic effect on the nociceptive threshold at 7 days after the end of treatment. Regarding anxiety-like behavior, it was noted that tDCS combined with exercise increased the number of entries in the open arms (EOA), and decreased the time spent in the closed arms (TCA). Of a biochemistry point-of-view, it was observed that the combination of tDCS and exercise, increased BDNF levels (7 days) and decreased IL-4 levels in the cerebral cortex. In the hippocampi, the combination of treatments triggered opposite effects throughout time; at 48h after the end of treatments, there was an increased BDNF levels, whilst at 7º day, it was observed a decreased BDNF and TNF-α levels. Regarding brainstem and spinal cord (7 days), the combination of both therapies increased the IL-4 levels, whilst in the sciatic nerve, there was an increased BDNF (48h) e IL-10 (7 days) levels promoted by both. Conclusion: In sum, our findings demonstrate that the combination of neuromodulatory techniques promote antinociceptive and anxiolytic-like effects. Therefore, such non-pharmacological approaches are promising adjuvants in the chronic pain management and its comorbidities. Additionally, it is possible to observe that these techniques promote the modulation of neurochemical parameters in a tissue, state or time-dependent fashion

A3 receptor agonist modulates IL-1β hippocampus levels in a rat model of neuropathic pain

Introduction: Considering the lack of specific treatments for neuropathic pain, this study aimed to evaluate the effect of a single dose of adenosine A3 receptor IB-MECA on inflammatory and neurotrophic parameters in rats subjected to a neuropathic pain model. Methods: 64 adult male Wistar rats were used. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve and the treatment consisted of a 0.5 μmol/kg dose of IB-MECA, a selective A3 adenosine receptor agonist, dissolved in 3% DMSO; vehicle groups received DMSO 3% in saline solution, and morphine groups received 5 mg/kg. Cerebral cortex and hippocampus IL-1β, BDNF, and NGF levels were determined by Enzyme-Linked Immunosorbent assay. Results: The main outcome was that a single dose of IB-MECA was able to modulate the IL-1β hippocampal levels in neuropathic pain induced by CCI and the DMSO increased IL-1β and NGF hippocampal levels in sham-operated rats. However, we did not observe this effect when the DMSO was used as vehicle for IB-MECA, indicating that IB-MECA was able to prevent the effect of DMSO. Conclusions: Considering that the IL-1β role in neuropathic pain and the contributions of the hippocampus are well explored, our result corroborates the relationship between the A3 receptor and the process of chronic pain maintenance

The electron-furfural scattering dynamics for 63 energetically open electronic states

14 págs.; 15 figs.We report on integral-, momentum transfer- and differential cross sections for elastic and electronically inelastic electron collisions with furfural (CHO). The calculations were performed with two different theoretical methodologies, the Schwinger multichannel method with pseudopotentials (SMCPP) and the independent atom method with screening corrected additivity rule (IAM-SCAR) that now incorporates a further interference (I) term. The SMCPP with N energetically open electronic states (N) at either the static-exchange (N ch-SE) or the static-exchange-plus-polarisation (N ch-SEP) approximation was employed to calculate the scattering amplitudes at impact energies lying between 5 eV and 50 eV, using a channel coupling scheme that ranges from the 1ch-SEP up to the 63ch-SE level of approximation depending on the energy considered. For elastic scattering, we found very good overall agreement at higher energies among our SMCPP cross sections, our IAM-SCAR+I cross sections and the experimental data for furan (a molecule that differs from furfural only by the substitution of a hydrogen atom in furan with an aldehyde functional group). This is a good indication that our elastic cross sections are converged with respect to the multichannel coupling effect for most of the investigated intermediate energies. However, although the present application represents the most sophisticated calculation performed with the SMCPP method thus far, the inelastic cross sections, even for the low lying energy states, are still not completely converged for intermediate and higher energies. We discuss possible reasons leading to this discrepancy and point out what further steps need to be undertaken in order to improve the agreement between the calculated and measured cross sections. ©2016 AIP Publishing LLCR.F.d.C., M.C.A.L., M.H.F.B., M.T.d.N.V., and M.A.P.L. acknowledge support from the Brazilian agency Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). M.T.d.N.V. acknowledges support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). D.B.J. thanks the Australian Research Council (ARC) for financial support provided through a Discovery Early Career Researcher Award. M.J.B. thanks the ARC for some financial support and also thanks CNPq for his “Special Visiting Professor” award at the Federal University of Juiz de Fora. G.G. thanks the Spanish Ministerio de Economia y Competitividad under Project No. FIS2012- 31230 and the European Union COST Action No. CM1301 for funding.Peer Reviewe

A3 receptor agonist modulates IL-1β hippocampus levels in a rat model of neuropathic pain

Introduction: Considering the lack of specific treatments to neuropathic pain, this study aimed to evaluate the effect of a single dose adenosine A3 receptor IB-MECA in the inflammatory and neurotrophic parameters of rats submitted to a neuropathic pain model. Methods: 64 adults male Wistar rats were used.  Neuropathic pain was induced by the chronic constriction injury (CCI) of sciatic nerve and the treatment consisted in one dose of 0.5 μmol/kg of a selective agonist of adenosine A3 receptor IB-MECA dissolved in 3% DMSO; vehicle groups received DMSO 3% in saline; morphine groups received 5mg/kg Cerebral cortex and hippocampus IL-1β, BDNF and NGF levels were determined by ELISA assay. Results: The key finding was that a single dose of IB-MECA was able to modulate the IL-1β hippocampus levels CCI and the DMSO increased IL-1β and NGF hippocampus levels in sham animals; however, when the DMSO as an IB-MECA vehicle, this effect was not observed, indicating that IB-MECA was able to prevent the effect of DMSO. Conclusions: Considering that the IL-1β role in neuropathic pain is quite explored, as well as the hippocampus contributions, our result corroborates the relationship of A3 receptor and the chronic pain maintenance process. @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-536870145 1107305727 0 0 415 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman",serif; mso-fareast-font-family:"Times New Roman";}.MsoChpDefault {mso-style-type:export-only; mso-default-props:yes;}div.WordSection1 {page:WordSection1;

Theoretical and experimental differential cross sections for electron impact excitation of the electronic bands of furfural

13 págs.; 8 figs.; 6 tabs.We report results from a joint experimental and theoretical investigation into electron scattering from the important industrial species furfural (CHO). Specifically, differential cross sections (DCSs) have been measured and calculated for the electron-impact excitation of the electronic states of CHO. The measurements were carried out at energies in the range 20-40 eV, and for scattered-electron angles between 10°and 90°. The energy resolution of those experiments was typically ∼80 meV. Corresponding Schwinger multichannel method with pseudo-potential calculations, for energies between 6-50 eV and with and without Born-closure, were also performed for a sub-set of the excited electronic-states that were accessed in the measurements. Those calculations were undertaken at the static exchange plus polarisation-level using a minimum orbital basis for single configuration interaction (MOB-SCI) approach. Agreement between the measured and calculated DCSs was qualitatively quite good, although to obtain quantitative accord, the theory would need to incorporate even more channels into the MOB-SCI. The role of multichannel coupling on the computed electronic-state DCSs is also explored in some detail. ©2016 AIP Publishing LLCR.F.C.N. thanks CNPq (Brazil) and the Science Without Borders Programme for opportunities to study abroad. D.B.J. thanks the Australian Research Council (ARC) for financial support provided through a Discovery Early Career Research Award, while M.J.B. also thanks the ARC for their support. M.J.B. and M.C.A.L. acknowledge the Brazilian agencies CNPq and FAPEMIG. P.L.-V. acknowledges the Portuguese Foundation for Science and Technology (FCTMEC) through Grant Nos. PTDC/FIS-ATO/1832/2012 and UIO/FIS/00068/2013. G.G. acknowledges partial financial support from the Spanish Ministry MINECO (Project No. FIS2012-31230) and the European Union COST Action No. CM1301 (CELINA). Finally, R.F.d.C., M.T.d.N.V., M.H.F.B., and M.A.P.L. acknowledge support from the Brazilian agency CNPq and M.T.d.N.V. also thanks FAPESP.Peer Reviewe

Low energy elastic and electronically inelastic electron scattering from biomolecules.

Reactions initiated by collisions with low-energy secondary electrons has been found to be the prominent\ud mechanism toward the radiation damage on living tissues through DNA strand breaks. Now it is widely accepted\ud that during the interaction with these secondary species the selective breaking of chemical bonds is triggered\ud by dissociative electron attachment (DEA), that is, the capture of the incident electron and the formation\ud of temporary negative ion states [1,2,3]. One of the approaches largely used toward a deeper understanding\ud of the radiation damage to DNA is through modeling of DEA with its basic constituents (nucleotide bases,\ud sugar and other subunits). We have tried to simplify this approach and attempt to make it comprehensible\ud at a more fundamental level by looking at even simple molecules. Studies involving organic systems such as\ud carboxylic acids, alcohols and simple ¯ve-membered heterocyclic compounds are taken as starting points for\ud these understanding. In the present study we investigate the role played by elastic scattering and electronic\ud excitation of molecules on electron-driven chemical processes. Special attention is focused on the analysis of\ud the in°uence of polarization and multichannel coupling e®ects on the magnitude of elastic and electronically\ud inelastic cross-sections. Our aim is also to investigate the existence of resonances in the elastic and electronically\ud inelastic channels as well as to characterize them with respect to its type (shape, core-excited or Feshbach),\ud symmetry and position. The relevance of these issues is evaluated within the context of possible applications\ud for the modeling of discharge environments and implications in the understanding of mutagenic rupture of DNA\ud chains. The scattering calculations were carried out with the Schwinger multichannel method (SMC) [4] and\ud its implementation with pseudopotentials (SMCPP) [5] at di®erent levels of approximation for impact energies\ud ranging from 0.5 eV to 30 eV.\ud References\ud [1] B. Boudai®a, P. Cloutier, D. Hunting, M. A. Huels and L. Sanche, Science 287, 1658 (2000). [2] X. Pan, P.\ud Cloutier, D. Hunting and L. Sanche, Phys. Rev. Lett. 90, 208102 (2003). [3] F. Martin, P. D. Burrow, Z. Cai,\ud P. Cloutier, D. Hunting and L. Sanche, Phys. Rev. Lett. 93, 068101 (2004). [4] K. Takatsuka and V. McKoy,\ud Phys. Rev. A 24, 2437 (1981); ibid. Phys. Rev. A 30, 1734 (1984). [5] M. H. F. Bettega, L. G. Ferreira and\ud M. A. P. Lima, Phys. Rev. A 47, 1111 (1993)

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