RESUMO
BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is the most commonly used and clinically relevant murine model for human multiple sclerosis (MS), a demyelinating autoimmune disease characterized by mononuclear cell infiltration into the central nervous system (CNS). The aim of the present study was to appraise the alterations, poorly documented in the literature, which may occur at the peripheral nervous system (PNS) level. METHODS: To this purpose, a multiple evaluation of peripheral nerve excitability was undertaken, by means of a minimally invasive electrophysiological method, in EAE mice immunized with the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, an experimental model for MS that reproduces, in animals, the anatomical and behavioral alterations observed in humans with MS, including CNS inflammation, demyelination of neurons, and motor abnormalities. Additionally, the myelin sheath thickness of mouse sciatic nerves was evaluated using transmission electronic microscopy. RESULTS: As expected, the mean clinical score of mice, daily determined to describe the symptoms associated to the EAE progression, increased within about 18 days after immunization for EAE mice while it remained null for all control animals. The multiple evaluation of peripheral nerve excitability, performed in vivo 2 and 4 weeks after immunization, reveals that the main modifications of EAE mice, compared to control animals, are a decrease of the maximal compound action potential (CAP) amplitude and of the stimulation intensity necessary to generate a CAP with a 50% maximum amplitude. In addition, and in contrast to control mice, at least 2 CAPs were recorded following a single stimulation in EAE animals, reflecting various populations of sensory and motor nerve fibers having different CAP conduction speeds, as expected if a demyelinating process occurred in the PNS of these animals. In contrast, single CAPs were always recorded from the sensory and motor nerve fibers of control mice having more homogeneous CAP conduction speeds. Finally, the myelin sheath thickness of sciatic nerves of EAE mice was decreased 4 weeks after immunization when compared to control animals. CONCLUSIONS: In conclusion, the loss of immunological self-tolerance to MOG in EAE mice or in MS patients may not be only attributed to the restricted expression of this antigen in the immunologically privileged environment of the CNS but also of the PNS.
Assuntos
Potenciais de Ação/fisiologia , Encefalomielite Autoimune Experimental/fisiopatologia , Condução Nervosa/fisiologia , Nervos Periféricos/fisiopatologia , Animais , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Nervos Periféricos/imunologia , Nervos Periféricos/patologiaRESUMO
Because environmental elements modify chronic pain development and endogenous mechanisms of pain control are still a great therapeutic source, we investigated the effects of an early exposure to environmental enrichment (EE) in a translational model of neuropathic pain. Young male rats born and bred in an enriched environment, which did not count on running wheel, underwent chronic constriction injury (CCI) of sciatic nerve. EE abolished neuropathic pain behavior 14 days after CCI. Opioid receptors' antagonism reversed EE-analgesic effect. ß-endorphin and met-enkephalin serum levels were increased only in EE-CCI group. Blockade of glucocorticoid receptors did not alter EE-analgesic effect, although corticosterone circulating levels were increased in EE animals. In the spinal cord, EE controlled CCI-induced serotonin increase. In DRG, EE blunted the expression of ATF-3 after CCI. Surprisingly, EE-CCI group showed a remarkable preservation of sciatic nerve fibers compared to NE-CCI group. This work demonstrated global effects induced by an EE protocol that explain, in part, the protective role of EE upon chronic noxious stimulation, reinforcing the importance of endogenous mechanisms in the prevention of chronic pain development.
Assuntos
Meio Ambiente , Neuralgia/prevenção & controle , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático/lesões , Animais , Sobrevivência Celular , Constrição Patológica , Endorfinas/sangue , Encefalinas/sangue , Hiperalgesia/patologia , Masculino , Fibras Nervosas/patologia , Neuralgia/etiologia , Neuralgia/patologia , Traumatismos dos Nervos Periféricos/patologia , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Nervo Isquiático/patologia , Medula Espinal/metabolismo , Suporte de CargaRESUMO
Neuropathic pain is a disease caused by structural and functional plasticity in central and peripheral sensory pathways that produce alterations in nociceptive processing. Currently, pharmacological treatment for this condition remains a challenge. Crotoxin (CTX), the main neurotoxin of Crotalus durissus terrificus rattlesnake venom, has well described prolonged anti-inflammatory and antinociceptive activities. In spite of its potential benefits, the toxicity of CTX remains a limiting factor for its use. SBA-15 is an inert nanostructured mesoporous silica that, when used as a vehicle, may reduce toxicity and potentiate the activity of different compounds. Based on this, we propose to conjugate crotoxin with SBA-15 (CTX:SBA-15) in order to investigate if when adsorbed to silica, CTX would have its toxicity reduced and its analgesic effect enhanced in neuropathic pain induced by the partial sciatic nerve ligation (PSNL) model. SBA-15 enabled an increase of 35% of CTX dosage. Treatment with CTX:SBA-15 induced a long-lasting reduction of mechanical hypernociception, without modifying the previously known pathways involved in antinociception. Moreover, CTX:SBA-15 reduced IL-6 and increased IL-10 levels in the spinal cord. Surprisingly, the antinociceptive effect of CTX:SBA-15 was also observed after oral administration. These data indicate the potential use of the CTX:SBA-15 complex for neuropathic pain control and corroborates the protective potential of SBA-15.
Assuntos
Analgésicos/uso terapêutico , Crotoxina/uso terapêutico , Neuralgia/tratamento farmacológico , Dióxido de Silício/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Animais , Crotoxina/administração & dosagem , Crotoxina/efeitos adversos , Hiperalgesia/tratamento farmacológico , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanoestruturas , Nociceptividade/efeitos dos fármacos , Neuropatia Ciática/tratamento farmacológico , Dióxido de Silício/administração & dosagem , Dióxido de Silício/efeitos adversos , Medula Espinal/metabolismoRESUMO
Advanced glycation end-products (AGEs) are proteins/lipids that are glycated upon sugar exposure and are often increased during inflammatory diseases such as osteoarthritis and neurodegenerative disorders. Here, we developed an extracellular matrix (ECM) using glycated type I collagen (ECM-GC), which produced similar levels of AGEs to those detected in the sera of arthritic mice. In order to determine whether AGEs were sufficient to stimulate sensory neurons, dorsal root ganglia (DRGs) cells were cultured on ECM-GC or ECM-NC-coated plates. ECM-GC or ECM-NC were favorable for DRG cells expansion. However, ECM-GC cultivated neurons displayed thinner F-actin filaments, rounded morphology, and reduced neuron interconnection compared to ECM-NC. In addition, ECM-GC did not affect RAGE expression levels in the neurons, although induced rapid p38, MAPK and ERK activation. Finally, ECM-GC stimulated the secretion of nitrite and TNF-α by DRG cells. Taken together, our in vitro glycated ECM model suitably mimics the in vivo microenvironment of inflammatory disorders and provides new insights into the role of ECM impairment as a nociceptive stimulus.
Assuntos
Técnicas de Cultura de Células/métodos , Colágeno Tipo I/metabolismo , Gânglios Espinais/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Ativação Enzimática , Glicosilação , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Nitritos/metabolismo , Fosforilação , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Background. Glial cells are implicated in the development of chronic pain and brain-derived neurotropic factor (BDNF) released from activated microglia contributes to the nociceptive transmission. Neural mobilization (NM) technique is a method clinically effective in reducing pain sensitivity. Here we examined the involvement of glial cells and BDNF expression in the thalamus and midbrain after NM treatment in rats with chronic constriction injury (CCI). CCI was induced and rats were subsequently submitted to 10 sessions of NM, every other day, beginning 14 days after CCI. Thalamus and midbrain were analyzed for glial fibrillary acidic protein (GFAP), microglial cell OX-42, and BDNF using Immunohistochemistry and Western blot assays. Results. Thalamus and midbrain of CCI group showed increases in GFAP, OX-42, and BDNF expression compared with control group and, in contrast, showed decreases in GFAP, OX-42, and BDNF after NM when compared with CCI group. The decreased immunoreactivity for GFAP, OX-42, and BDNF in ventral posterolateral nucleus in thalamus and the periaqueductal gray in midbrain was shown by immunohistochemistry. Conclusions. These findings may improve the knowledge about the involvement of astrocytes, microglia, and BDNF in the chronic pain and show that NM treatment, which alleviates neuropathic pain, affects glial cells and BDNF expression.