RESUMO
Surgical intervention is necessary following nerve trauma. Tubular prostheses can guide growing axons and inserting substances within these prostheses can be positive for the regeneration, making it an alternative for the current standard tools for nerve repair. Our aim was to investigate the effects of fibrin glue BthTL when combined with a synthetic TNF mimetic-action peptide on nerve regeneration. Male Wistar rats suffered left sciatic nerve transection. For repairing, we used empty silicon tubes (n = 10), tubes filled with fibrin glue BthTL (Tube + Glue group, n = 10) or tubes filled with fibrin glue BThTL mixed with TNF mimetic peptide (Tube + Glue + Pep group, n = 10). Animals were euthanized after 45 days. We collected nerves to perform immunostaining (neurofilament, GAP43, S100-ß, NGFRp75 and Iba-1), light and transmission electron microscopy (for counting myelinated, unmyelinated and degenerated fibers; and for the evaluation of morphometric aspects of regenerated fibers) and collagen staining. All procedures were approved by local ethics committee (protocol 063/17). Tube + Glue + Pep group showed intense inflammatory infiltrate, higher Iba-1 expression, increased immunostaining for NGFRp75 receptor (which characterizes Schwann cell regenerative phenotype), higher myelin thickness and fiber diameter and more type III collagen deposition. Tube + Glue group showed intermediate results between empty tube and Tube + Glue + Pep groups for anti-NGFRp75 immunostaining, inflammation and collagen; on fiber counts, this group showed more degenerate fibers and fewer unmyelinated axons than others. Empty tube group showed superiority only in GAP43 immunostaining. A combination of BthTL glue and TNF mimetic peptide induced greater axonal regrowth and remyelination.
Assuntos
Adesivo Tecidual de Fibrina , Regeneração Nervosa/efeitos dos fármacos , Peptidomiméticos/administração & dosagem , Peptidomiméticos/farmacologia , Nervos Periféricos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia , Animais , Axônios/efeitos dos fármacos , Colágeno/metabolismo , Imuno-Histoquímica , Masculino , Bainha de Mielina/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Peptidomiméticos/química , Ratos , Ratos Wistar , Células de Schwann/efeitos dos fármacos , Células de Schwann/ultraestrutura , Nervo Isquiático/lesões , Fator de Necrose Tumoral alfa/químicaRESUMO
BACKGROUND: It is uncertain whether vitamin B-12 supplementation can improve neurophysiologic function in asymptomatic elderly with low vitamin B-12 status or whether folate status affects responses to vitamin B-12 supplementation. OBJECTIVE: We assessed the effects of a single intramuscular injection of 10 mg vitamin B-12 (which also contained 100 mg vitamin B-6 and 100 mg vitamin B-1) on vitamin B-12 status and neurophysiologic function in elderly community-dwelling Chileans with low serum vitamin B-12 concentrations who were consuming bread fortified with folic acid. DESIGN: A pretreatment and posttreatment study was conducted in 51 participants (median ± SD age: 73 ± 3 y; women: 47%) with serum vitamin B-12 concentrations <120 pmol/L at screening. Vitamin B-12 status was defined by combining vitamin B-12, plasma total homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin into one variable [combined indicator of vitamin B-12 status (cB-12)]. The response to treatment was assessed by measuring cB-12 and neurophysiologic variables at baseline and 4 mo after treatment. RESULTS: Treatment increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001) and reduced plasma tHcy and serum MMA (P < 0.001). Treatment produced consistent improvements in conduction in myelinated peripheral nerves; the sensory latency of both the left and right sural nerves improved on the basis of faster median conduction times of 3.1 and 3.0 ms and 3.3 and 3.4 ms, respectively (P < 0.0001). A total of 10 sensory potentials were newly observed in sural nerves after treatment. Participants with high serum folate at baseline (above the median, ≥33.9 nmol/L) had less improvement in cB-12 (P < 0.001) than did individuals whose serum folate was less than the median concentration (i.e., with a concentration <33.9 nmol/L). CONCLUSION: Asymptomatic Chilean elderly with poor vitamin B-12 status displayed improved conductivity in myelinated peripheral nerves after vitamin B-12 treatment and an interaction with folate status, which was detected only with the use of cB-12. This trial was registered at www.controlled-trials.com as ISRCTN02694183.
Assuntos
Suplementos Nutricionais , Ácido Fólico/sangue , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Deficiência de Vitamina B 12/tratamento farmacológico , Vitamina B 12 , Idoso , Chile , Feminino , Alimentos Fortificados , Homocisteína/sangue , Humanos , Masculino , Ácido Metilmalônico/sangue , Fibras Nervosas Mielinizadas/fisiologia , Estado Nutricional , Nervos Periféricos/fisiologia , Vitamina B 12/sangue , Vitamina B 12/farmacologia , Vitamina B 12/uso terapêutico , Deficiência de Vitamina B 12/sangue , Complexo Vitamínico B/sangue , Complexo Vitamínico B/farmacologia , Complexo Vitamínico B/uso terapêuticoRESUMO
Manganese (Mn) is able to cross the blood-brain barrier and induces functional and structural alterations during the intoxication by this metal. Therefore, the effects of chronic administration of Mn in the caudate nucleus of mice were evaluated by electron microscopy. Male albino mice were injected intraperitoneally with MnCl2 (5 mg/kg/d) 5 d per week during 9 weeks. The control group received only 0.9% of NaCl solution. The caudate nuclei were extracted and subsequently processed to be observed on a conventional transmission electron microscope at 2, 4, 6, and 9 weeks after treatment. A high percentage of vacuolated and swollen mitochondria were found throughout all the analyzed periods. Myelin disarrangement and ultrastructural alterations related to edema were observed increased in Mn-treated mice at week 9. Granular degeneration of myelin at week 9 accompanied with deposition of electron dense granules in the neuropil was also observed. Edema in neuropil and glial cells was detected from week 2 to week 9 accompanied by swollen mitochondria. Neuronal bodies, synaptic terminals, and perivascular cells were found swollen. Decreased electron density in postsynaptic areas and decreased and dispersed synaptic vesicles in presynaptic areas were noted in Mn-treated animals. Some neurons from Mn-treated mice showed cisternae dilation of the Golgi apparatus. These results suggest that Mn-treatment produces structural alterations in the caudate nucleus that could be responsible for some of the neurotoxic effects of this metal.
Assuntos
Núcleo Caudado/ultraestrutura , Cloretos/toxicidade , Bainha de Mielina/ultraestrutura , Fibras Nervosas Mielinizadas/ultraestrutura , Animais , Núcleo Caudado/efeitos dos fármacos , Masculino , Compostos de Manganês , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Bainha de Mielina/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Espectrofotometria AtômicaRESUMO
Endogenous palmitoylethanolamide (PEA) has a key role in pain modulation. Central or peripheral PEA can reduce nociceptive behavior, but no study has yet reported a descending inhibitory effect on the neuronal nociceptive activity of Aδ- and C-fibers. This study shows that intracisternal PEA inhibits the peripheral nociceptive responses of dorsal horn wide dynamic range cells (i.e., inhibition of Aδ- and C-fibers), an effect blocked by spinal methiothepin. These results suggest that a descending analgesic mechanism mediated by the serotonergic system could be activated by central PEA.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Analgésicos/farmacologia , Etanolaminas/farmacologia , Nociceptores/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Corno Dorsal da Medula Espinal/citologia , Amidas , Animais , Estimulação Elétrica , Laminectomia , Masculino , Metiotepina/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Espaço Subaracnóideo/efeitos dos fármacos , Espaço Subaracnóideo/fisiologia , Fatores de TempoRESUMO
BACKGROUND: Axonal regeneration depends on many factors, such as the type of injury and repair, age, distance from the cell body and distance of the denervated muscle, loss of surrounding tissue and the type of injured nerve. Experimental models use tubulisation with a silicone tube to research regenerative factors and substances to induce regeneration. Agarose, collagen and DMEM (Dulbecco's modified Eagle's medium) can be used as vehicles. In this study, we compared the ability of these vehicles to induce rat sciatic nerve regeneration with the intent of finding the least active or inert substance. The experiment used 47 female Wistar rats, which were divided into four experimental groups (agarose 4%, agarose 0.4%, collagen, DMEM) and one normal control group. The right sciatic nerve was exposed, and an incision was made that created a 10 mm gap between the distal and proximal stumps. A silicone tube was grafted onto each stump, and the tubes were filled with the respective media. After 70 days, the sciatic nerve was removed. We evaluated the formation of a regeneration cable, nerve fibre growth, and the functional viability of the regenerated fibres. RESULTS: Comparison among the three vehicles showed that 0.4% agarose gels had almost no effect on provoking the regeneration of peripheral nerves and that 4% agarose gels completely prevented fibre growth. The others substances were associated with profuse nerve fibre growth. CONCLUSIONS: In the appropriate concentration, agarose gel may be an important vehicle for testing factors that induce regeneration without interfering with nerve growth.
Assuntos
Colágeno/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Próteses e Implantes , Neuropatia Ciática/cirurgia , Sefarose/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/patologia , Silicones/uso terapêutico , Fatores de TempoRESUMO
Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia-ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use. In this work, we have determined whether intranasal (iN) administration of human aTf provides neuroprotection to the neonatal mouse brain following a cerebral hypoxic-ischemic event. Apotransferrin was infused into the naris of neonatal mice and the HI insult was induced by right common carotid artery ligation followed by exposure to low oxygen concentration. Our results showed that aTf was successfully delivered into the neonatal HI brain and detected in the olfactory bulb, forebrain and posterior brain 30 min after inhalation. This treatment successfully reduced white matter damage, neuronal loss and astrogliosis in different brain regions and enhanced the proliferation and survival of oligodendroglial progenitor cells (OPCs) in the subventricular zone and corpus callosum (CC). Additionally, using an in vitro hypoxic model, we demonstrated that aTf prevents oligodendrocyte progenitor cell death by promoting their differentiation. In summary, these data suggest that iN administration of aTf has the potential to be used for clinical treatment to protect myelin and to induce remyelination in demyelinating hypoxic-ischemic events in the neonatal brain.
Assuntos
Apoproteínas/administração & dosagem , Lesões Encefálicas/prevenção & controle , Hipóxia-Isquemia Encefálica/patologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Transferrina/administração & dosagem , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , Administração Intranasal , Fatores Etários , Animais , Animais Recém-Nascidos , Antígenos/metabolismo , Proteínas Relacionadas à Autofagia , Lesões Encefálicas/etiologia , Bromodesoxiuridina/metabolismo , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Colchicina/farmacologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Citocalasina B/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Humanos , Hipóxia/tratamento farmacológico , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Proteínas de Filamentos Intermediários/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Proteína Básica da Mielina/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina , Neurogênese/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteoglicanas/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Fatores de TempoRESUMO
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System which is characterized by multifocal demyelinated lesions dispersed throughout the brain. Although white matter lesions have been the most extensively studied, cortical demyelinaton lesions are also detected in MS brains. Cuprizone (CPZ)-induced demyelination in rodents has been widely used as a model for MS. Most of these studies focus on oligodendrocyte-rich structures, such as the corpus callosum (CC) and the cerebellar peduncles. However, it has been recently described that CPZ administration in mice also produces cortical demyelination, resembling some of the lesions found in MS patients. In this work we used CPZ-demyelinating model in Wistar rats to study demyelination in cortical forebrain areas. At the ultrastructural level, demyelination in the cortex was observed before detectable myelin loss in the subcortical white matter. During the course of CPZ intoxication Myelin Basic Protein immunodetection was decreased in cortical layers I-III due to a reduction in the number of cortical oligodendrocytes (OL). Oligodendroglial loss in CPZ-intoxicated rats correlated with an increase in the number of Glial Fibrillary Acidic Protein positive astrocytes and a shift in the location of Carbonic Anhydrase II from OL to astrocytes. After removal of CPZ from the diet, we evaluate intranasal Thyroid hormone (TH) effects on the progression of cortical lesions. As previously reported in the CC, TH treatment also accelerates remyelination rate in the cortex compared to rats undergoing spontaneous remyelination. Our results suggest that manipulation of TH levels could be considered as a strategy to promote remyelination process in the cortex and to prevent neuronal irreversible damage in patients suffering from MS.
Assuntos
Córtex Cerebral/patologia , Doenças Desmielinizantes/induzido quimicamente , Bainha de Mielina/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Hormônios Tireóideos/administração & dosagem , Administração Intranasal , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Córtex Cerebral/efeitos dos fármacos , Cuprizona , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos , Ratos WistarRESUMO
OBJECTIVE: To analyze the influence of the topical use of basic fibroblast growth factor (bFGF) in the regeneration of the facial nerve in rats. STUDY DESIGN: Experimental study. MATERIALS AND METHODS: Twenty-eight Wistar adult male rats underwent complete section of the facial nerve trunk, followed by end-to-end anastomosis with epineural sutures. An osmotic minipump equipped with a delivery catheter was implanted subcutaneously near the neural anastomosis. During the subsequent 14 days, 14 animals received a solution containing 25 microg/ml of bFGF, 250 UI/ml of sodium heparin, and 1,000 microg/ml of human albumin diluted in Ringer lactate, and 14 animals received a control solution of the same components without bFGF. To evaluate facial nerve regeneration, the number of myelinated fibers evident on histologic sections was counted on the 14th (7 experimental and 8 control animals) and the 28th days (7 experimental and 6 control animals) after surgery, and the facial movements of vibrissae and the blink reflex were evaluated on alternate days until the 28th day. RESULTS: On histologic evaluation, the number of myelinated fibers was similar between groups on the 14th day and greater in the group that received bFGF on the 28th day. Behavioral evaluation showed that the animals of the bFGF group presented better functional results between the 6th and 16th days for the blink test and the 14th to the 16th days for vibrissae movements. CONCLUSION: This study showed that the regeneration of the facial nerve occurred earlier and resulted in significantly more myelinated nerve fibers in the animals that received topical bFGF.
Assuntos
Traumatismos do Nervo Facial/tratamento farmacológico , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Administração Cutânea , Animais , Piscadela/efeitos dos fármacos , Contagem de Células , Traumatismos do Nervo Facial/patologia , Traumatismos do Nervo Facial/fisiopatologia , Masculino , Fibras Nervosas Mielinizadas/patologia , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Vibrissas/efeitos dos fármacosRESUMO
Experimental autoimmune encephalomyelitis (EAE), an induced model of Multiple Sclerosis presents spinal cord demyelination, axonal pathology and neuronal dysfunction. Previous work has shown that progesterone attenuated the clinical severity, demyelination and neuronal dysfunction of EAE mice (Garay et al., J. Steroid Biochem. Mol. Biol., 2008). Here we studied if progesterone also prevented axonal damage, a main cause of neurological disability. To this end, some axonal parameters were compared in EAE mice pretreated with progesterone a week before immunization with MOG(40-54) and in a group of steroid-free EAE mice. On day 16th after EAE induction, we determined in both groups and in control mice: a) axonal density in semithin sections of the spinal cord ventral funiculus; b) appearance of amyloid precursor protein (APP) immunopositive spheroids as an index of damaged axons; c) levels of the growth associated protein GAP43 mRNA and immunopositive cell bodies, as an index of aberrant axonal sprouting. Steroid-naive EAE mice showed decreased axonal density, shrunken axons, abundance of irregular vesicular structures, degenerating APP+ axons, increased expression of GAP43 mRNA and immunoreactive protein in motoneurons. Instead, EAE mice receiving progesterone treatment showed increased axonal counts, high proportion of small diameter axons, reduced APP+ profiles, and decreased GAP43 expression. In conclusion, progesterone enhanced axonal density, decreased axonal damage and prevented GAP43 hyperexpression in the spinal cord of EAE mice. Thus, progesterone also exerts protective effects on the axonal pathology developing in EAE mice.
Assuntos
Axônios/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Proteína GAP-43/genética , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Fármacos Neuroprotetores/metabolismo , Progesterona/metabolismo , Progestinas/metabolismo , Progestinas/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Resultado do Tratamento , Degeneração Walleriana/tratamento farmacológico , Degeneração Walleriana/metabolismo , Degeneração Walleriana/patologiaRESUMO
INTRODUCTION AND HYPOTHESIS: The authors quantified the nerve fibers in the bladder wall of ovariectomized rats with and without estradiol replacement. METHODS: This study was conducted on 40 Wistar rats (3 months old). Group 1: remained intact; Group 2: underwent bilateral ovariectomy, and after 30 days was started on subcutaneous sesame oil replacement (0.2 ml per day) for 90 days; Group 3: sham-operated, and after 30 days was started on subcutaneous sesame oil replacement (0.2 ml per day) for 90 days; Group 4: bilateral ovariectomy, and after 30 days was started on subcutaneous injection of 17ß-estradiol (10 µg/kg body weight) for 90 days. S-100 was used to stain nerves myelinized fibers on paraffin rat bladder sections. The G-50 grid system was used to quantitatively analyze the fibers. CONCLUSION: Long-term estrogen deprivation caused significant changes in bladder innervations, which can be characterized by a decreased number of nerve fibers by 65% (p < 0.001).
Assuntos
Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Bexiga Urinária/inervação , Animais , Denervação , Feminino , Ovariectomia , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
Recent results implicate a new original mechanism involving oxytocin (OT), as a mediator via descending fibers of the paraventricular hypothalamic nucleus (PVN), in antinociception and analgesia. In rats electrical stimulation of the PVN or topical application of OT selectively inhibits A-delta and C fiber responses in superficial dorsal horn neurons, and this inhibition is reversed by a selective OT antagonist. However, little is known about the mechanisms and the spinal elements participating in this phenomenon. Here we show that topical application of bicuculline blocks the effects produced by PVN electrical stimulation or OT application. PVN electrical stimulation also activates a subpopulation of neurons in lamina II. These PVN-On cells are responsible for the amplification of local GABAergic inhibition. This result reinforces the suggestion that a supraspinal descending control of pain processing uses a specific neuronal pathway in the spinal cord in order to produce antinociception involving a GABAergic interneuron. Moreover, the topical administration of naloxone or a mu-opiate receptor antagonist beta-funaltrexamine only partially blocks the inhibitory effects produced by OT application or PVN electrical stimulation. Thus, this OT mechanism only involves opiate participation to a minor extent. The OT-specific, endogenous descending pathway represents an interesting mechanism to resolve chronic pain problems in special the neuropathic pain.
Assuntos
Hipotálamo/metabolismo , Neurônios/metabolismo , Nociceptores/metabolismo , Ocitocina/metabolismo , Medula Espinal/metabolismo , Raízes Nervosas Espinhais/metabolismo , Animais , Bicuculina/farmacologia , Vias Eferentes/citologia , Vias Eferentes/metabolismo , Estimulação Elétrica , Antagonistas GABAérgicos/farmacologia , Hipotálamo/citologia , Antagonistas de Entorpecentes/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/ultraestrutura , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/metabolismo , Fibras Nervosas Amielínicas/ultraestrutura , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/citologia , Nociceptores/citologia , Nociceptores/efeitos dos fármacos , Peptídeos Opioides/metabolismo , Ocitocina/farmacologia , Dor/metabolismo , Dor/fisiopatologia , Células do Corno Posterior/citologia , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Ratos , Ratos Wistar , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Raízes Nervosas Espinhais/citologia , Raízes Nervosas Espinhais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
OBJECTIVES: Based on evidence that pregnant women with multiple sclerosis (MS) show a decline in the relapse rate during the third trimester and an increase during the first 3 months postpartum, the suggestion was made that high levels of circulating sex steroids are responsible for pregnancy-mediated neuroprotection. As both estradiol (E(2)) and progesterone exert neuroprotective and myelinating effects on the nervous system, the effects of sex steroids were studied in the experimental autoimmune encephalomyelitis (EAE) model of MS. METHODS: EAE was induced in female C57BL/6 mice by administration of a myelin oligodendrocyte protein (MOG(40-45)) peptide. Clinical signs of EAE, myelin protein expression and neuronal parameters were determined in mice with or without hormonal treatment. RESULTS: Progesterone given prior to EAE induction attenuated the clinical scores of the disease, slightly delayed disease onset and decreased demyelination foci, according to luxol fast blue staining (LFB), myelin basic protein (MBP) and proteolipid protein (PLP) and mRNA expression. Motoneuron expression of Na,K-ATPase mRNA was also enhanced by progesterone. In turn, combined E(2) plus progesterone therapy more effectively prevented neurological deficits, fully restored LFB staining, MBP and PLP immunoreactivity and avoided inflammatory cell infiltration. On the neuronal side, steroid biotherapy increased brain-derived neurotrophic factor (BDNF) mRNA. CONCLUSION: Early treatment with progesterone alone or more evidently in combination with E(2) showed a clinical benefit and produced myelinating and neuroprotective effects in mice with MOG(40-45)-induced EAE. Therefore, sex steroids should be considered as potential novel therapeutic strategies for MS.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Estradiol/farmacologia , Esclerose Múltipla/tratamento farmacológico , Sistemas Neurossecretores/imunologia , Progesterona/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Estradiol/metabolismo , Estradiol/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Proteína Básica da Mielina/efeitos dos fármacos , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Proteína Proteolipídica de Mielina/efeitos dos fármacos , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Progesterona/metabolismo , Progesterona/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
We have used a model of iron deficiency in the rat to analyze the effects of a disruption in iron availability on oligodendroglial cell (OLGc) maturation and myelinogenesis and to explore the possible beneficial influence of an intracranial injection (ICI) of apotransferrin (aTf) at 3 days of age on this process. Studies carried out on postnatal days 17 and 24 showed that iron deficiency produced a decrease in myelin proteins and lipids at 24 days of age. Immunohistochemistry showed that in untreated iron-deficient (ID) rats, the immunoreactivity of anti-adenomatous polyposis coli (APC) and anti-MBP antibodies decreased markedly with reference to normal controls, whereas in ID rats treated with an ICI of aTf, the immunoreactivity of these markers increased. A similar situation occurred with the immunoreactivity of H-ferritin. In primary OLGc cultures from ID rats, there was a high number of cells positive to the antibody against the polysialylated form of the cell surface glycoprotein NCAM (PSA-NCAM) compared with in OLGc cultures prepared from normal controls or from ID animals treated with aTf. The number of MBP+ cells in cultures from ID rats increased after treatment with aTf. The presence of lipid rafts evaluated with a specific anti-protein prion cellular (PrPc) antibody showed a smaller number of PrPc-positive structures in ID rat cultures. Treatment of the ID animals with a single ICI of aTf stimulated myelination, producing a significant correction in the different biochemical parameters affected by ID.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/patologia , Apoproteínas/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Fibras Nervosas Mielinizadas/patologia , Transferrina/uso terapêutico , Anemia Ferropriva/sangue , Animais , Animais Recém-Nascidos , Apoproteínas/farmacologia , Células Cultivadas , Doenças Desmielinizantes/sangue , Modelos Animais de Doenças , Feminino , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Transferrina/farmacologiaRESUMO
Following acute and chronic neurodegenerative disorders, a cascade of pathological events including inflammatory response, excitotoxicity and oxidative stress induces secondary tissue loss in both gray and white matter. Axonal damage and demyelination are important components of the white matter demise during these diseases. In spite of this, a few studies have addressed the patterns of inflammatory response, axonal damage and demyelination following focal ischemic damage to the central nervous system (CNS). In the present study, we describe the patterns of inflammatory response, axonal damage and myelin impairment following microinjections of 10 pmol of endothelin-1 into the rat striatum. Animals were perfused at 1 day, 3 days and 7 days after injection. 20 mum sections were stained by hematoxylin and immunolabeled for neutrophils (anti-MBS-1), activated macrophages/microglia (anti-ED1), damaged axons (anti-betaAPP) and myelin (anti-MBP). The evolution of acute inflammation was quantitatively assessed by cell counts in different survival times. There was recruitment of both neutrophils and macrophages to the damaged striatal parenchyma with maximum recruitment at 1 day and 7 days, respectively. Progressive myelin impairment in the striatal white matter tracts has been observed mainly at later survival times. beta-APP+ endbulbs were not present in all evaluated time points. These results suggest that progress myelin impairment in the absence of damage to axonal cylinder is a feature of white matter pathology following endothelin-1-induced focal striatal ischemia.
Assuntos
Isquemia Encefálica/fisiopatologia , Corpo Estriado/fisiopatologia , Doenças Desmielinizantes/fisiopatologia , Encefalite/fisiopatologia , Endotelina-1/toxicidade , Fibras Nervosas Mielinizadas/patologia , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Biomarcadores/análise , Biomarcadores/metabolismo , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/patologia , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/fisiologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Progressão da Doença , Encefalite/induzido quimicamente , Encefalite/patologia , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/metabolismo , Microcirculação/fisiopatologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microinjeções , Proteína Básica da Mielina/análise , Proteína Básica da Mielina/metabolismo , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Ratos WistarRESUMO
In the somatosensory system, the flow of sensory information is regulated at early stages by presynaptic inhibition. Recent findings have shown that the mechanisms generating the primary afferent depolarization (PAD) associated with presynaptic inhibition are complex, with some components mediated by a non-spiking mechanism. How sensory inputs carried by neighbouring afferent fibres interact to regulate the generation of PAD, and thus presynaptic inhibition, is poorly known. Here, we investigated the interaction between neighbouring primary afferents for the generation of PAD in an in vitro preparation of the turtle spinal cord. To monitor PAD we recorded the dorsal root potential (DRP), while the simultaneous cord dorsum potential (CDP) was recorded to assess the population postsynaptic response. We found that the DRP and the CDP evoked by a primary afferent test stimulus was greatly reduced by a conditioning activation of neighbouring primary afferents. This depression had early and late components, mediated in part by GABAA and GABAB receptors, since they were reduced by bicuculline and SCH 50911 respectively. However, with the selective stimulation of C and Adelta fibres in the presence of TTX, the early and late depression of the DRP was replaced by facilitation of the GABAergic and glutamatergic components of the TTX-resistant DRP. Our findings suggest a subtle lateral excitatory interaction between primary afferents for the generation of PAD mediated by a non-spiking mechanism that may contribute to shaping of information transmitted by C and Adelta fibres in a spatially confined scale in analogy with the retina and olfactory bulb.
Assuntos
Potenciais de Ação/fisiologia , Inibição Neural/fisiologia , Neurônios Aferentes/metabolismo , Medula Espinal/metabolismo , Raízes Nervosas Espinhais/metabolismo , Transmissão Sináptica/fisiologia , Potenciais de Ação/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/metabolismo , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Antagonistas GABAérgicos/farmacologia , Ácido Glutâmico/metabolismo , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Receptores de GABA/efeitos dos fármacos , Receptores de GABA/metabolismo , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia , Medula Espinal/anatomia & histologia , Raízes Nervosas Espinhais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Tartarugas , Ácido gama-Aminobutírico/metabolismoRESUMO
The ultrastructural change that characterizes the onset of Wallerian degeneration is the disintegration of axoplasmic microtubules and neurofilaments, which are converted into an amorphous and granular material, followed by myelin breakdown. The mechanism underlying such processes is an increase in the amount of intracellular calcium, leading to activation of proteases called calpains. The aim of this study was to evaluate by quantitative ultrastructural analysis whether nerve fibers can be preserved by the use of an exogenous inhibitor of these proteases (calpain inhibitor-2, Mu-F-hF-FMK), after optic nerve crush. For that, the left optic nerves of opossums, Didelphis aurita, were crushed with the aid of a fine forceps, and half of them received a calpain inhibitor mixed with Elvax resin. Ninety-six hours after the lesion, the animals were reanesthetized and transcardially perfused, and the optic nerves were removed, the right ones being used as normal nerves. Afterward, the optic nerves were dissected and processed for routine transmission electron microscopy and quantitative and statistical analysis. The results of this analysis showed that the group that received the calpain inhibitor presented a reduction of astrogliosis, maintaining the optic nerve structure in an organized state; a significant decrease in the number of degenerating fibers; and a significant increase in the number of fibers with preserved cytoskeleton and preservation of axonal and myelin area and integrity, reducing the enlargement and edema of the axon. In conclusion, our findings suggest that calpain inhibitor is able to provide neuroprotection of the central nervous system fibers after a crush lesion.
Assuntos
Axônios/efeitos dos fármacos , Calpaína/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Degeneração Neural/prevenção & controle , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Oligopeptídeos/farmacologia , Nervo Óptico/efeitos dos fármacos , Animais , Axônios/enzimologia , Axônios/ultraestrutura , Inibidores de Cisteína Proteinase/uso terapêutico , Compressão Nervosa/métodos , Degeneração Neural/enzimologia , Degeneração Neural/patologia , Fibras Nervosas Mielinizadas/enzimologia , Fibras Nervosas Mielinizadas/ultraestrutura , Oligopeptídeos/uso terapêutico , Gambás , Nervo Óptico/enzimologia , Nervo Óptico/ultraestruturaRESUMO
Cem ratos norvégicus, machos, com aproximadamente 3 meses de idade foram distribuídos por sorteio em 2 grupos experimentais: Grupo Controle (GC): com 50 ratos sadios, não diabéticos e Grupo Diabético (GD): com 50 ratos diabéticos, induzidos pela aloxana, sem qualquer tratamento. Cada grupo foi dividido em 5 subgrupos com 10 ratos cada e sacrificados com 1, 3, 6, 9 e 12 meses de seguimento, respectivamente. Parâmetros clínicos (peso, ingestão hídrica e alimentar, e diurese) e laboratoriais (glicemia, glicose urinária e insulina) foram documentados em todos os momentos de avaliação. Um segmento do nervo ciático foi obtido de cada animal, em ambos os grupos, para estudo à MO. e ME. Alterações clínicas e laboratoriais significativas (P<0,01), compatíveis com diabetes grave, foram observadas em todos os animais do GD a partir do 4§ dia após a indução. Ratos de ambos os grupos apresentaram alterações no número de fibras mielínicas e nos depósitos intraaxonais de glicogênio que não diferiram, estatisticamente, aos 1, 3 e 6 meses de seguimento. Entretanto, aos 9 e 12 meses, ratos do GD apresentaram diminuição significativa no número de fibras mielínicas, com aumento do número de fibras mielínicas de menor calibre, quando comparados com ratos do GC (P<0,05). Grânulos de glicogênio intraaxonais também foram mais acentuados em ratos do GD no 9§ e 12§ mês de seguimento. Não foram observadas diferenças na densidade de fibras amielínicas ou alterações ultraestruturais significativas entre os dois grupos, em relação aos espaços intraaxonais e endoneurais, bainhas de mielina e células de Schwann durante todo o estudo.
Assuntos
Animais , Masculino , Ratos , Aloxano/efeitos adversos , Modelos Animais de Doenças , Nervo Isquiático , Neuropatias Diabéticas/induzido quimicamente , Seguimentos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Neuropatias Diabéticas/diagnósticoAssuntos
Diazepam/toxicidade , Troca Materno-Fetal/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Neurópilo/efeitos dos fármacos , Animais , Feminino , Colículos Inferiores/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Gravidez , Núcleo Rubro/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Fatores de TempoRESUMO
La disponibilidad de los anestésicos locales en el organismo depende de procesos fisiológicos que sufren continuos cambios durante los períodos de desarrollo. Esto implica que el uso de los anestésicos locales en pediatría no sea sencillo, por las diferencias que aparecen en los procesos farmacocinéticos durante el crecimiento. Para su uso correcto en pediatría es necesario conocer la farmacocinética y farmacodinamia de los anestésicos locales en el recién nacido y en el niño, así como la influencia que tienen ciertas patologías sobre ellos
Assuntos
Humanos , Lactente , Pré-Escolar , Criança , Recém-Nascido , Anestesia por Condução , Anestésicos Locais/farmacocinética , Anestésicos Locais/farmacologia , Anestésicos Locais/metabolismo , Anestésicos Locais/toxicidade , Raquianestesia/estatística & dados numéricos , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Pediatria , Anestesia Geral , Bupivacaína/administração & dosagem , Lidocaína/administração & dosagem , Fatores de RiscoRESUMO
La disponibilidad de los anestésicos locales en el organismo depende de procesos fisiológicos que sufren continuos cambios durante los períodos de desarrollo. Esto implica que el uso de los anestésicos locales en pediatría no sea sencillo, por las diferencias que aparecen en los procesos farmacocinéticos durante el crecimiento. Para su uso correcto en pediatría es necesario conocer la farmacocinética y farmacodinamia de los anestésicos locales en el recién nacido y en el niño, así como la influencia que tienen ciertas patologías sobre ellos(AU)